National PBM Drug Monograph

Ambrisentan (Letairis™)

September 2008

VHA Pharmacy Benefits Management Services and the Medical Advisory Panel

*The purpose of VACO PBM drug monographs is to provide a comprehensive
drug review for making formulary decisions. These documents will be
updated when new clinical data warrant additional formulary discussion.
Documents will be placed in the Archive section when the information is
deemed to be no longer current.*

# Executive Summary: 

-   Ambrisentan is an endothelin receptor antagonist (ERA) with high
    selectivity for the endothelin A (ET~A)~ receptor subtype.

-   Ambrisentan is indicated for the treatment of pulmonary arterial
    hypertension (PAH) World Health Organization (WHO) Group 1
    (including idiopathic PAH \[IPAH\] and PAH associated with
    connective tissue disease \[CTD\]; see Table 1) in patients with WHO
    functional class II or III symptoms (see Table 3) to improve
    exercise capacity and delay clinical worsening.

-   Ambrisentan has been evaluated in two similarly designed phase-3,
    placebo-controlled trials, ARIES-1 and ARIES-2. In both trials,
    ambrisentan treatment was associated with significant improvements
    in the 6-minute walk distance (6MWD) compared to placebo after 12
    weeks of treatment (placebo-adjusted means of 45m \[95% CI
    24.3-64.9\] with 5 mg, and 53m with 10 mg \[95% CI 28.8-76.2\],
    combined data from ARIES-C). A significant delay in clinical
    worsening was also observed with ambrisentan treatment in ARIES-1.

-   Long-term safety and efficacy was evaluated in the ARIES-E study, an
    extension of ARIES-1 and ARIES-2, with a mean duration of exposure
    of 38.6 ±26.5 weeks. Overall, ambrisentan was well tolerated. Per
    exploratory analysis of patients who received at least 48 weeks of
    ambrisentan monotherapy, mean 6MWD improvements appeared to be
    maintained.

-   Results from the uncontrolled, open-label AMB-222 study suggest that
    treatment with ambrisentan may be considered in patients who
    previously discontinued ERA therapy due to asymptomatic LFT
    abnormalities once levels return to normal.

-   Ambrisentan was generally well tolerated in clinical trials. The
    most common adverse events (AEs) reported were mild to moderate in
    nature and included peripheral edema, nasal congestion, sinusitis,
    flushing, palpitations, and GI effects. Serious adverse reactions
    may include hepatotoxicity, decreases in hemoglobin, and fluid
    retention requiring intervention.

-   In addition to baseline LFTs and pregnancy test (when appropriate),
    hemoglobin must be checked prior to initiation of ambrisentan
    treatment, at one month, and periodically thereafter. Continuous,
    monthly monitoring of LFTs and pregnancy tests (when appropriate)
    are required. Post marketing reports of fluid retention requiring
    intervention (diuretic, fluid management, hospitalization) warrant
    close monitoring, particularly in the first few weeks of treatment.

-   No clinically relevant drug interactions with ambrisentan and
    warfarin or sildenafil have been identified. However, in-vitro study
    suggests that ambrisentan is metabolized by CYP3A4, 2C19 and
    UGT1A9S, 2B7S, and 1A3S, and is a substrate of OATP and P-gp.
    Clinical drug interaction studies with strong inhibitors or inducers
    of these pathways have not been conducted, and the effects of
    co-administration with ambrisentan are unknown. Caution should be
    used when administering ambrisentan with a strong inhibitor or
    inducer of these pathways.

-   Available as an oral tablet, ambrisentan should be initiated at 5 mg
    once daily with consideration of titrating to 10 mg once daily if
    tolerated.

-   Ambrisentan is an FDA Pregnancy Category X drug and is
    contraindicated in women who are or may become pregnant. Due to the
    risks of hepatotoxicity and teratogenicity, ambrisentan is only
    available through a restricted distribution program, the Letairis
    Education and Access Program (LEAP). (Phone: 1-866-664-LEAP;
    Website: [www.letairis.com](http://www.letairis.com/) )

# Introduction {#introduction .Style-Heading-1-+-Black}

The purposes of this monograph are to (1) evaluate the available
evidence of safety, tolerability, efficacy, cost, and other
pharmaceutical issues that would be relevant to evaluating ambrisentan
for possible addition to the VA National Formulary; (2) define its role
in therapy; and (3) identify parameters for its rational use in the VA.

**[Background]{.underline}**^1,2^

In addition to general or adjunctive therapy for PAH, newer treatments
have become available that aim to delay disease progression and improve
functional status, symptoms, and survival. The second ERA approved in
the US, ambrisentan, is an oral formulation given once daily to decrease
symptoms of PAH and delay clinical worsening.

The WHO classification of pulmonary hypertension (PH) divides the
disease into 5 groups. Group 1 encompasses PAH and includes IPAH,
familial PAH (FPAH), and PAH associated with CTD, Human Immunodeficiency
Virus (HIV), or anorexient use (See Table 1).

Table 1. WHO Clinical Classification of Pulmonary Hypertension (Revised
Venice 2003)^3^

+------+---------------------------------------------------------------+
| G    | Classification                                                |
| roup |                                                               |
+------+---------------------------------------------------------------+
| 1    | Pulmonary arterial hypertension (PAH)                         |
|      |                                                               |
|      | -   Idiopathic (IPAH)                                         |
|      |                                                               |
|      | -   Familial (FPAH)                                           |
|      |                                                               |
|      | -   Associated (APAH)                                         |
|      |                                                               |
|      |     -   Collagen vascular disease                             |
|      |                                                               |
|      |     -   Congenital systemic-to-pulmonary shunts               |
|      |                                                               |
|      |     -   Portal hypertension                                   |
|      |                                                               |
|      |     -   HIV infection                                         |
|      |                                                               |
|      |     -   Drugs and toxins                                      |
|      |                                                               |
|      |     -   Other                                                 |
|      |                                                               |
|      | -   Associated with significant venous or capillary           |
|      |     involvement                                               |
|      |                                                               |
|      |     -   Pulmonary veno-occlusive disease                      |
|      |                                                               |
|      |     -   Pulmonary capillary hemangiomatosis                   |
|      |                                                               |
|      | -   Persistent pulmonary hypertension of the newborn          |
+------+---------------------------------------------------------------+
| 2    | Pulmonary venous hypertension (PH due to left heart disease)  |
+------+---------------------------------------------------------------+
| 3    | Pulmonary hypertension associated with disorders of the       |
|      | respiratory system or hypoxemia                               |
+------+---------------------------------------------------------------+
| 4    | Pulmonary hypertension due to chronic thrombotic or embolic   |
|      | disease (CTEPH)                                               |
+------+---------------------------------------------------------------+
| 5    | Miscellaneous pulmonary hypertension (inflammation or         |
|      | nonthrombotic obstruction)                                    |
+------+---------------------------------------------------------------+

The pathophysiology of PAH is incompletely understood, and thought to
include genetic susceptibility, insult and inflammation of the pulmonary
vasculature, toxins, and/or hypoxia. The result is a combination of
vasoconstriction, smooth-muscle and endothelial hyperproliferation, and
in situ thrombus formation in the pulmonary vessels, eventually leading
to right ventricular failure and death.

Three major pathways have been targeted in an attempt to alter the
course of PAH: 1) the endothelin (ET) pathway (ERAs); 2) the nitric
oxide (NO) pathway (exogenous NO, phosphodiesterase type 5 (PDE-5
inhibitors); and 3) the prostacyclin pathway (prostacyclin derivatives).
In addition, calcium channel antagonists are used for their vasodilator
properties in a small proportion of patients who show vasoreactivity
under right heart catheterization.

# Pharmacology/Pharmacokinetics ^2,4,5^ {#pharmacologypharmacokinetics-245 .Style-Heading-1-+-Black}

Endothelin-1 (ET-1) is an endogenous peptide that has been shown to have
potent vasoconstrictive effects as well as mitogenic, pro-inflammatory,
and pro-fibrotic effects. In patients with PAH, abnormally high levels
of ET-1 have been detected. The effects of ET-1 are mediated through
ET~A~ and ET~B~ receptor subtypes. Activation of ET~A~ receptors results
in vasoconstriction and smooth-muscle cell proliferation, while
activation of ET~B~ receptors induces vasodilation and mediates ET-1
clearance. ERAs block the effects of ET-1 at the receptor site.
Ambrisentan is an ERA with high selectivity for the ET~A~ receptor
subtype, while bosentan is a dual receptor antagonist (ET~A~ and ET~B~)
available in the US. The clinical impact of ET~A~ selectivity is
unknown.

Table 2 Pharmacokinetics

  ----------------- ---------------------------------------------------------
  **Parameter**     **Drug**

  Protein Binding   99%

  Bioavailability   unknown

  Cmax              2 hrs

  Metabolism        unclear; in-vitro data suggest ambrisentan is metabolized
                    by CYP3A4, 2C19, and UGT1A9S, 2B7S, and 1A3S, and is a
                    substrate of OATP, P-gp

  Elimination       non-renal

  Half-life         15 hr terminal; 9 hr effective
  ----------------- ---------------------------------------------------------

CYP=cytochrome P450 enzyme; UGT=uridine 5'-diphosphate
glucuronosyltransferases; OATP=organic anion transport protein;
P-gp=P-glycoprotein

# FDA Approved Indication(s) and Off-label Uses^4^

Ambrisentan is indicated for the treatment of WHO Group 1 PAH (see
Table 1) in patients with WHO functional class II or III symptoms (See
Table 3) to improve exercise capacity and delay clinical worsening.

# Current VA National Formulary Alternatives

There are currently no ERAs on the VA National Formulary.

# Dosage and Administration^4,5^

Therapy with ambrisentan should be initiated at 5 mg once daily. If
tolerated, increasing the dose to 10 mg once daily should be considered.
Ambrisentan may be administered without regard to meals. Tablets should
not be split, chewed or crushed.

**Special Populations**

*Women of Childbearing Potential*

Ambrisentan belongs to the FDA Pregnancy Category X and is thus
contraindicated in women who are or may become pregnant. A negative
pregnancy test is required prior to initiation of therapy and monthly
thereafter. Pregnancy must be prevented with the use of two reliable
forms of contraception (or tubal sterilization or IUD insertion). (See
Precautions/Contraindications)

*Use in Nursing Mothers*

It is unknown whether ambrisentan is excreted in human breast milk. Use
of ambrisentan in breastfeeding women is not recommended.

*Geriatric Use*

Only 21% of patients in ARIES-1 and ARIES-2 were ≥65 years of age.
Peripheral edema was more common in the geriatric population. In
subgroup analysis, patients ≥65 years of age had smaller improvements in
6MWD compared to younger patients.

*Renal Impairment*

Dosage adjustment of ambrisentan in the presence of mild to moderate
renal impairment is not required. The impact of severe renal impairment
or hemodialysis on ambrisentan exposure is unknown.

*Hepatic Impairment*

Use of ambrisentan is not recommended in patients with moderate to
severe hepatic impairment, as significant alterations in the
pharmacokinetics of the drug are expected. Caution should be exercised
in using ambrisentan in patients with mild hepatic impairment. Dose
reductions and closer monitoring may be necessary if elevated LFTs occur
during treatment (See Precautions/Contraindications).

**Access**

Because of the risks of hepatotoxicity and teratogenic effects,
ambrisentan is only available through a restricted distribution program,
LEAP (Letairis Education and Access Program). To prescribe or distribute
ambrisentan, providers and pharmacies must enroll with LEAP (by calling
1-866-664-LEAP (5327) or visiting
[www.letairis.com](http://www.letairis.com/) for additional information
and forms). Providers and patients must be educated on the risks of
ambrisentan treatment including hepatotoxicity and teratogenicity. Women
of childbearing potential must be educated and counseled on the use of
two reliable forms of contraception (unless the patient has had tubal
sterilization or IUD insertion). Baseline and monthly LFTs (for all
patients) and pregnancy tests (for women of childbearing age) must be
obtained and reviewed.

# Efficacy^4,5^ 

## Efficacy Measures

Patients with PAH commonly present with symptoms of dyspnea on exertion,
weakness, and fatigue. Progression of the disease leads to right heart
failure and death. Measures of efficacy in clinical trials evaluating
PAH treatment commonly include indicators of improved functional or
exercise capacity. The standard endpoint used in many clinical trials is
the 6 minute walk distance (6MWD), an inexpensive, non-invasive,
reproducible evaluation where patients walk at a pace that they can
tolerate, as far as possible in 6 minutes. Further, the 6MWD has been
shown to be a prognostic indicator of mortality.^5^ The following
clinical measures were also evaluated in clinical trials with
ambrisentan:

-   Borg Dyspnea Index (BDI)^7^ -- patient-perceived exertion scale
    rated from 0 (no exertion) to 10 (almost maximal exertion)

-   Clinical worsening -- predefined as death, lung transplant,
    hospitalization for PAH, atrial septostomy, study withdrawal due to
    addition of PAH drugs, or early escape. Early escape criteria
    allowed for patients to prematurely discontinue the study due to
    lack of efficacy. If the patient completed 4 weeks of treatment and
    2 of the following criteria were met, early escape was permitted:
    ≥20% decrease from baseline in 6MWD, advancement of ≥1WHO functional
    class, worsening right ventricular failure, rapidly progressing
    cardiogenic, hepatic, or renal failure, refractory systolic
    hypotension.

-   Time to clinical worsening (TTCW) -- time to clinical worsening
    event

-   SF 36 Health Survey -- a multi-purpose, 36-question generic survey
    that scores on physical and mental health measures

-   WHO functional class status^8^ -- adapted from the New York Heart
    Association classification

    ^Table\ 3.\ WHO\ Functional\ Class\ Assessment8^

  ------- ---------------------------------------------------------------
  Class   Description

  I       No limitation in physical activity; ordinary physical activity
          does not cause dyspnea or fatigue

  II      Slight limitations in physical activity; ordinary physical
          activity produces dyspnea, fatigue, chest pain, or
          near-syncope; no symptoms at rest

  III     Marked limitation of physical activity; less than ordinary
          physical activity produces dyspnea, fatigue, chest pain, or
          near-syncope; no symptoms at rest

  IV      Unable to perform any physical activity without symptoms;
          dyspnea and/or fatigue present at rest; discomfort increased by
          any physical activity
  ------- ---------------------------------------------------------------

## Summary of efficacy findings^4,5,9^ (See Appendix 1 for further details) 

The efficacy of ambrisentan has been evaluated in two similarly designed
phase-3 clinical trials, ARIES-1 and ARIES-2. A pre-specified combined
analysis of these two trials is reported in ARIES-C. ARIES-E is an
extension trial including patients from ARIES-1 and ARIES-2. In
addition, long term ambrisentan exposure is being examined in AMB 220-E,
an extension of a smaller phase 2 study. No head-to-head trials have
been conducted with other ERAs or other classes of drugs known to be
affective in PAH. Only results from ARIES-1 and ARIES-2 trials have been
published.^9^

ARIES-1 and ARIES-2 were similarly designed, randomized, double-blind,
placebo-controlled, multi-center, phase 3 clinical trials evaluating the
efficacy and safety of different doses of ambrisentan in patients with
IPAH or PAH associated with CTD, HIV, or anorexients. Both studies
investigated the primary endpoint of change from baseline in 6MWD after
12 weeks of treatment compared to placebo. Secondary efficacy endpoints
included TTCW and change in BDI, SF 36 Health Survey physical
functioning scale, and WHO functional class. Concurrent PAH therapy with
anticoagulants, diuretics, oxygen, digoxin, calcium-channel antagonists
was permitted.

In ARIES-1, 201 patients were randomized to one of three arms: 5 or 10
mg ambrisentan orally once daily or placebo. In the predominantly female
study population, approximately two-thirds of the patients had IPAH, 35%
had WHO class I/II symptoms, and 65% had WHO class III/IV symptoms.
After 12 weeks of treatment, significant improvements in 6MWD from
baseline were observed in both the 5 and 10 mg treatment groups compared
to placebo, with relative changes of 30.6m \[95% CI 2.9-58.3\] and 51.4m
\[95% CI 26.6-76.2\] respectively. An absolute mean decline of -7.8m
noted in the placebo group increased the relative change seen with the
treatment groups. After 4 weeks of treatment, a dose response effect was
evident. In the pre-specified TTCW analysis, a non-significant trend of
improvement was noted with ambrisentan treatment (6/134 patients in
ambrisentan group vs. 6/67 patients in the placebo group experienced
clinical worsening, with an ARR of 4.5%; NNT=22). Statistically
significant improvements were demonstrated in the combined ambrisentan
group vs. placebo in WHO functional class and BDI, but no difference was
observed in the SF 36 Health Survey physical function scale.

In ARIES-2, 192 patients were randomized to one of three groups: 2.5 or
5 mg of ambrisentan orally once daily or placebo. The majority of the
study population was female; 65% of patients had IPAH, 46% had WHO class
I/II symptoms, and 54% had class III/IV symptoms. Significant
improvements in 6MWD from baseline to 12 weeks were demonstrated in both
the 2.5 and 5 mg ambrisentan groups compared to placebo, with relative
changes of 32.3m \[95% CI 1.5-63.1\] and 59.4m \[95% CI 296.-89.3\]. An
absolute mean decline of -10.1m in 6MWD was observed in the placebo
group, increasing the relative change seen in both treatment groups.
Significant delay in TTCW was observed at week 12 in the combined
ambrisentan group vs. placebo (6/127 vs. 14/65 patients experienced
clinical worsening respectively; ARR 17%; NNT 6). Significant
improvements were noted with ambrisentan treatment vs. placebo in the SF
36 Health Survey and BDI, and a favorable but nonsignificant trend was
observed in WHO functional class.

In the combined analysis, ARIES-C, 393 patients were included. The
integrated population was predominantly female and Caucasian with a mean
age of 50 years. Overall, approximately 64% of patients had IPAH, while
the majority of the non-IPAH population had PAH associated with
connective tissue disease. Approximately 40% of patients had WHO class
I/II symptoms and 60% had class III/IV symptoms, with the great majority
falling into class II and III. The mean baseline 6MWD for all subjects
was 346m (SD ±80.1m). Of note, WHO class II patients had higher baseline
6MWD than class III patients. Dose dependent and significant increases
in 6MWD from baseline vs. placebo were demonstrated after 12 weeks of
treatment in the 2.5 mg, 5 mg and 10 mg groups respectively: 31m \[95%
CI 5.6-56.7\], 45m \[95% CI 24.3-64.9\], and 53m \[95% CI 28.8-76.2\].
There was a mean decrease in 6MWD in the placebo group of -9m. Subgroup
analysis suggested that men and non-IPAH groups may have a lower
response in the 6MWD, particularly at the 2.5 mg dose. In the combined
ambrisentan groups, significant delays in TTCW and improvements in WHO
functional class and BDI were observed.

ARIES-E was a long-term extension study of ARIES-1 and ARIES-2, where
patients receiving ambrisentan continued to receive blinded treatment
for 24 additional weeks, and those receiving placebo were randomized to
begin active treatment according to the respective study protocol (n=361
enrolled).^5,9^ The primary objective of the study was to assess safety,
but efficacy endpoints were evaluated as a secondary objective. In an
exploratory analysis of 280 patients who received ambrisentan
monotherapy for at least 48 weeks, the mean change in 6MWD appeared to
be maintained (40 m \[95% CI 33-48 m\] at 12 weeks and 39 m \[95% CI
29-49 m\] at 48 weeks).^9^ In AMB 220-E (n=54), an ongoing open-label
extension study, 6MWD was maintained after \>2 years in the combined
ambrisentan group (1 mg, 2.5 mg, 5 mg, 10 mg doses), with a mean
increase of +55.9m from baseline. Survival probabilities after 1, 2, and
3 years of treatment were 93%, 87%, and 85% respectively.

In all ARIES studies, 6MWD were not evaluated at trough ambrisentan
levels. With an effective half life of 9 hours, a theoretical concern is
that the therapeutic effect of ambrisentan may not be sustained
throughout the entire dosing interval. Additional studies to clarify
this issue are expected. At present, ambrisentan should be administered
no more than once daily. If desired effects are not achieved, use of
another agent that has been studied with more frequent dosing regimens
is recommended.

# Adverse Events (Safety Data)^4,5,9^

Safety data for ambrisentan includes a total of 483 patients with PAH.
Ambrisentan was generally well tolerated. The most common adverse
reactions reported were mild to moderate in nature and included
peripheral edema, nasal congestion, sinusitis, flushing, palpitations,
and GI effects, which are similar to those reported with other drugs in
the ERA class. Serious adverse events and adverse events leading to
discontinuation not related to PAH were comparable between ambrisentan
and placebo treated patients. In a subgroup analysis, peripheral edema
was more frequently reported in elderly patients receiving ambrisentan
vs. younger patients.

> Table 4. ARIES-1 and ARIES-2: Tolerability and adverse events
> occurring in \>3%
>
> ^of\ PAH\ patients\ receiving\ ambrisentan\ and\ at\ a\ greater\ frequency\ vs.\ placebo4,9^

+------------------------------------+----------------+----------------+
|                                    | **Placebo**    | *              |
|                                    |                | *Ambrisentan** |
|                                    | **(n=132)**    |                |
|                                    |                | **(n=261)**    |
+------------------------------------+----------------+----------------+
| Treatment discontinuation due to   | 4 (3%)         | 6 (2.3%)       |
| AE                                 |                |                |
+------------------------------------+----------------+----------------+
| Serious Adverse Events             | 22 (16.7%)     | 25 (9.6%)      |
+------------------------------------+----------------+----------------+
| Adverse Event                      |                |                |
+------------------------------------+----------------+----------------+
| Peripheral edema                   | 14 (11%)       | 45 (17%)       |
+------------------------------------+----------------+----------------+
| Nasal congestion                   | 2 (2%)         | 15 (6%)        |
+------------------------------------+----------------+----------------+
| Sinusitis                          | 0              | 8 (3%)         |
+------------------------------------+----------------+----------------+
| Flushing                           | 1 (1%)         | 10 (4%)        |
+------------------------------------+----------------+----------------+
| Palpitations                       | 3 (2%)         | 12 (5%)        |
+------------------------------------+----------------+----------------+
| Nasopharyngitis                    | 1 (1%)         | 9 (3%)         |
+------------------------------------+----------------+----------------+
| Abdominal pain                     | 1 (1%)         | 8 (3%)         |
+------------------------------------+----------------+----------------+
| Constipation                       | 2 (2%)         | 10 (4%)        |
+------------------------------------+----------------+----------------+
| Dyspnea                            | 4 (3%)         | 11 (4%)        |
+------------------------------------+----------------+----------------+
| Headache                           | 18 (14%)       | 38 (15%)       |
+------------------------------------+----------------+----------------+

Long term safety of ambrisentan was evaluated in the ARIES-E trial, an
extension of ARIES-1 and ARIES-2. A total of 383 patients received
ambrisentan for a mean duration of 38.6 ±26.5 weeks, including 22
patients who received at least one dose of ambrisentan but did not
enroll in ARIES-E. Comparisons of adverse events between doses are
limited, as dosage adjustments were permitted after 24 weeks. The most
commonly occurring severe adverse event was right ventricular failure.
Of the 21 deaths reported, 20 were considered unrelated to ambrisentan
and 1 was considered possibly due to ambrisentan. The majority of the
deaths were due to progressive right ventricular or respiratory failure.

^Table\ 5.\ ARIES-E:\ Tolerability,\ adverse\ events,\ and\ deaths5^

+-----------------------------------------------+----------------------+
|                                               | **Ambrisentan**      |
|                                               |                      |
|                                               | **all doses**        |
|                                               |                      |
|                                               | **(n=383)**          |
|                                               |                      |
|                                               | **n (%)**            |
+-----------------------------------------------+----------------------+
| Discontinuation due to AE                     | 36 (9.4)             |
+-----------------------------------------------+----------------------+
| Discontinuation due to non-improvement or     | 8 (2.1)              |
| worsening of PAH                              |                      |
+-----------------------------------------------+----------------------+
| Discontinuation due to early escape from      | 5 (1.3)              |
| ARIES-1 or ARIES-2                            |                      |
+-----------------------------------------------+----------------------+
| Any severe AE                                 | 105 (27.4)           |
+-----------------------------------------------+----------------------+
| Death                                         | 21 (5.5)             |
+-----------------------------------------------+----------------------+
| Treatment emergent LFT elevations \>3x ULN    | 6 (1.6)              |
+-----------------------------------------------+----------------------+
| Discontinuation of ambrisentan (LFTs \>8x     | 1                    |
| ULN)                                          |                      |
+-----------------------------------------------+----------------------+
| Discontinued concomitant drug                 | 1                    |
+-----------------------------------------------+----------------------+
| Transient abnormalities (continued            | 4                    |
| ambrisentan)                                  |                      |
+-----------------------------------------------+----------------------+
| Common AEs                                    |                      |
+-----------------------------------------------+----------------------+
| Peripheral edema                              | 102 (26.6)           |
+-----------------------------------------------+----------------------+
| Headache                                      | 68 (17.8)            |
+-----------------------------------------------+----------------------+
| Upper respiratory tract infection             | 45 (11.7)            |
+-----------------------------------------------+----------------------+
| Dizziness                                     | 42 (11)              |
+-----------------------------------------------+----------------------+
| Arthralgia                                    | 41 (10.7)            |
+-----------------------------------------------+----------------------+

Long term safety of ambrisentan has also been evaluated in AMB 220-E, an
ongoing, open-label extension of a phase 2 trial (n=54). After more than
2 years of follow-up, 18.5% discontinued therapy due to an AE, 44%
experienced a serious SAE, and 9.3% died, although none of the serious
AEs or deaths was found to be related to study drug. Significant AST
and/or ALT elevations occurred in three patients: one resulted in
discontinuation of ambrisentan, one resulted in temporary interruption
of therapy, and one was unconfirmed upon retest with no further
intervention.

The safety of ambrisentan in PAH patients who had previously
discontinued ERA therapy due to serum aminotransferase elevations was
evaluated in AMB-222. This phase 2, open-label, multicenter study
enrolled 36 patients, the majority of whom had WHO class III symptoms
and had received bosentan, while the remainder had received sitaxsentan
or both. Median exposure to ambrisentan was 54 weeks. One patient (2.8%;
CI 0.1-14.5) had an unconfirmed ALT level of 3.17x upper limit of normal
(ULN) at 12 weeks of exposure, which was managed by temporary
interruption of therapy. Ambrisentan was restarted after 10 days and
titrated up to 10 mg daily with no further occurrences of elevated LFTs.
No additional patients had LFT elevations \>3x ULN. Two patients
discontinued the drug due to side effects (pain in the extremity and
palpitations). Other side effects were similar to that reported in other
clinical trials with ambrisentan.

# Precautions/Contraindications^4,5^

**Black Box Warning**

Included in the prescribing information for ambrisentan is a black box
warning regarding the potential for liver injury and contraindication in
pregnancy. See below for further information.

## Precautions

*Hepatic Toxicity*

Treatment with ERAs including ambrisentan has been associated with liver
toxicity, primarily observed as elevations of aspartate aminotransferase
(AST) and alanine aminotransferase (ALT) and occasionally accompanied by
elevated bilirubin. Aminotransferase elevations \>3x ULN with bilirubin
elevations of \>2x ULN may be a sign of potentially serious hepatic
injury.

In clinical trials with ambrisentan, the 12-week incidence AST or ALT
elevations \>3x ULN and \>8x ULN was 0.8% and 0.2% respectively (n=483).
At one year, the rate of AST or ALT elevations of \>3x ULN and \>8x ULN
was 2.8% and 0.5% respectively. One case of aminotransferase elevations
of \>3x ULN and bilirubin \>2x ULN occurred.

Due to the potential for hepatic toxicity, which may occur following
prolonged treatment as reported with another ERA, baseline and monthly
monitoring of LFTs is required during ambrisentan treatment. Ambrisentan
should not be initiated in patients with baseline AST or ALT elevations
\>3x ULN, as monitoring for hepatic injury may be more difficult.
Treatment with ambrisentan should be discontinued if AST or ALT
elevations are accompanied by clinical symptoms of hepatic toxicity
(i.e., nausea, vomiting, fever, jaundice, right upper quadrant pain).

Recommended management of therapy in the setting of elevated LFTs:

-   If aminotransferase elevations are \>3 and ≤5x ULN, recheck labs. If
    confirmed, ambrisentan therapy should be interrupted or the dose
    reduced. Recheck LFTs every 2 weeks until aminotransferases are
    below 3x ULN.

-   If aminotransferase elevations are \>5 and ≤8x ULN, ambrisentan
    therapy should be discontinued. Monitor LFTs until levels are below
    3x ULN. Re-initiation of ambrisentan may be considered with more
    frequent LFT monitoring.

-   If aminotransferase elevations are \>8x ULN, ambrisentan should be
    discontinued and not restarted.

-   If AST or ALT is elevated in the setting of elevated bilirubin (\>2x
    ULN) or if accompanied by clinical symptoms of liver toxicity,
    ambrisentan therapy should be discontinued and not restarted.

*Hematologic Changes*

Decreases in hemoglobin and hematocrit have been reported with ERAs
including ambrisentan. In clinical trials with ambrisentan, the mean
decrease in hemoglobin was 0.8 g/dL after 12 weeks of treatment.
Considerable decreases in hemoglobin, defined as \>15% from baseline and
below normal limits, occurred in 7% of ambrisentan-treated patients vs.
4% of patients receiving placebo. Hemoglobin decreases typically
occurred within the first weeks of treatment followed by stabilization.
The mechanism for the hematologic changes is unclear. Hemoglobin must be
measured prior to initiation of ambrisentan, at one month, and
periodically thereafter. Discontinuation of therapy should be considered
in the setting of significantly decreased hemoglobin when other causes
have been ruled out.

*Peripheral Edema and Fluid Retention*

An ERA class effect as well as a clinical manifestation of PAH,
peripheral edema has been reported with increased frequency in
ambrisentan vs. placebo treated patients and in elderly vs. younger
patients in clinical trials. Post-marketing reports of fluid retention
requiring intervention (i.e., diuretic, fluid management,
hospitalization for decompensating heart failure) occurring within weeks
of initiation of ambrisentan treatment have been received. Ambrisentan
should be considered along with other potential causes if significant
fluid retention, with or without weight gain, develops. High morbidity
combined with failure of diuretic therapy may necessitate
discontinuation of ambrisentan.

**Contraindications**

Ambrisentan is a Pregnancy Category X medication and is contraindicated
in women who are or may become pregnant. Teratogenicity is a class
effect of the ERAs and has been demonstrated in animal studies with
ambrisentan. Women of childbearing potential must have a negative
pregnancy test prior to initiating ambrisentan and be tested monthly
thereafter. Two reliable forms of contraception must be used during
treatment with ambrisentan (unless the patient has had tubal
sterilization or IUD insertion).

# Look-alike / Sound-alike (LA / SA) Error Risk Potential

The VA PBM and Center for Medication Safety is conducting a pilot
program which queries a multi-attribute drug product search engine for
similar sounding and appearing drug names based on orthographic and
phonologic similarities, as well as similarities in dosage form,
strength and route of administration. Based on similarity scores as well
as clinical judgment, the following drug names [may]{.underline} be
potential sources of drug name confusion:

  ------------------ ----------------------------------------------------
  **Drug Name**      **LA/SA Drug Name**

  **Ambrisentan      Ambien 5 and 10 mg tablets
  (generic) 5 and 10 
  mg tablets**       

                     Ambenonium Chloride 10 mg tablets

  **Letairis (brand) Cialis 10 mg tablets
  5 and 10 mg        
  tablets**          

                     Levitra 5 and 10 mg tablets

                     Luveris 75 IU injection
  ------------------ ----------------------------------------------------

# Drug Interactions^4,5^

In vitro information suggests that ambrisentan is metabolized by CYP3A4,
2C19, and UGT1A9S, 2B7S, and 1A3S, and is a substrate of OATP and P-gp.
Clinical drug interaction studies with strong inhibitors or inducers of
these pathways have not been conducted, and the effects of
co-administration with ambrisentan are unknown. Caution should be used
when ambrisentan is co-administered with the following:

-   Strong inhibitors of CYP3A4 (atazanavir, clarithromycin, indinavir,
    itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir,
    saquinavir, telithromycin)

-   Strong inhibitors of CYP2C19 (omeprazole)

-   Strong inducers of CYP3A and 2C19 (rifampin)

-   Strong inhibitors of the transporters P-gp (cyclosporine A) and OATP
    (cyclosporine A, rifampin)

*Warfarin*

No clinically relevant effects on prothrombin time (PT), International
Normalized Ratio (INR) or warfarin pharmacokinetics were observed in
healthy volunteers or PAH patients co-administered warfarin and
ambrisentan. No dosage adjustments are required.

*Sildenafil*

In healthy volunteers, no clinically relevant pharmacokinetic changes
were detected when single doses of sildenafil and ambrisentan were
given. No dosage adjustments for sildenafil or ambrisentan are needed
when the two drugs are administered together.

# Acquisition Costs

Table 6. Acquisition Costs of Ambrisentan and Comparator Treatments
(prices as of 9/08; for updated pricing info go to
[vaww.pbm.va.gov]{.underline})

  ------------- ------------ ---------------------- ----------------- -----------------------
  **Drug**      **Dose**     **Cost/Day/patient**   **Cost/30-Day     **Cost/Year/Patient**
                                                    Fill/Patient**    

  Ambrisentan   5 mg/day     \$65.07                \$1,951.97        \$23,748.97

  Ambrisentan   10 mg/day    \$65.07                \$1,951.97        \$23,748.97

  Bosentan      62.5 mg BID  \$64.57                \$1,937.16 (+\$50 \$23,568.78 (+\~\$600
                                                    admin fee per     admin fees)
                                                    fill)             

  Bosentan      125 mg BID   \$65.06                \$1,951.96 (+\$50 \$23,748.85 (+\~\$600
                                                    admin fee per     admin fees)
                                                    fill)             

  Iloprost      2.5-5 mcg    \$132.72 - 199.08      \$3,981.60 --     \$48,442.80 --
                INH 6-9x/day                        5,972.40          72,664.20 (+\~\$3,200
                                                                      device)

  Sildenafil    20 mg TID    \$19.86                \$595.81          \$7,248.90
  (Revatio)                                                           

  Sildenafil    25 mg TID    \$10.19                \$305.70          \$3,719.35^†^
  (Viagra)                                                            
  ------------- ------------ ---------------------- ----------------- -----------------------

^†^Using ½ tab of 50 mg strength

# Conclusions

Ambrisentan is a selective ERA that has been shown to be effective in
increasing exercise capacity and may delay clinical worsening in
patients with WHO group 1 PAH with WHO class II/III symptoms, as
demonstrated in two double-blind, placebo-controlled trials of 12 weeks
duration. Preliminary longer-term study suggests that efficacy and
safety with ambrisentan is maintained. As observed in one open-label
study, ambrisentan may be considered an alternative in patients who
develop significant LFT elevations on bosentan. No head-to-head trials
with ambrisentan and other PAH therapies have been conducted to date,
making the determination of its place in therapy difficult. The clinical
significance of ET~A~ selectivity with ambrisentan has yet to be
determined. Additional investigation is needed to further clarify the
potential for drug interactions as well as whether once daily
administration is the optimal dosing strategy for ambrisentan. As with
all ERAs, close monitoring is necessary.

**[Place in Therapy]{.underline}**

-   Given data from published, randomized, placebo-controlled clinical
    trials of 12 weeks duration, ambrisentan has been shown to be an
    effective and generally well tolerated therapeutic option in the
    treatment of WHO Group 1 PAH in patients with WHO functional class
    II or III symptoms.

-   Ambrisentan may be considered in patients who have previously
    discontinued ERA therapy due to asymptomatic LFT elevations.

-   Although no head-to-head studies have been conducted, it appears
    that ambrisentan is associated with a similar efficacy and side
    effect profile as bosentan through indirect comparisons. Further
    study and additional patient exposure is needed to clarify
    differences between agents regarding drug interaction and
    hepatotoxic potential, although it appears that ambrisentan may be
    associated with a lower incidence of LFT abnormalities (LFT
    elevations of \>3x ULN occurring in 2.8% of ambrisentan and 11% of
    bosentan patients; indirect comparison from respective product
    information only).

-   With a different mechanism of action and side effect profile,
    sildenafil may be a preferred alternative in many PAH patients,
    particularly WHO functional class II or III. Drug costs at FDA
    approved doses are significantly lower than with ERA therapy;
    however, if higher doses of sildenafil are used, costs may be
    comparable to that of ERA treatment. In the preliminary guidance
    from the National Institute for Health and Clinical Excellence
    (NICE), the use of sildenafil is recommended for the treatment of
    PAH unless the drug is contraindicated, ineffective, or not
    tolerated, where treatment with an ERA is recommended.^10^

-   Prior to consideration of ERA treatment, a comprehensive pulmonary
    hypertension work-up must be completed. A definitive diagnosis of
    WHO Group 1 PAH must be confirmed by right-heart catheterization,
    and other causes of pulmonary hypertension must be excluded (i.e.,
    left heart disease, chronic thromboembolic disease, lung disease, or
    chronic hypoxemia). Initial work-up must also include baseline
    assessment of exercise capacity with 6MWD (unless patient is unable
    to perform) and functional status (e.g., WHO functional class, other
    supportive measures as appropriate).

-   Patients considered for ambrisentan treatment should be managed
    under the care of an experienced provider in the management of PAH
    (i.e., cardiology/pulmonary service).

-   Follow-up assessment of response to therapy should occur on a
    regular basis in patients with PAH and include evaluation of
    exercise capacity (unless patient is unable to perform) and
    functional status (e.g., 6MWD, WHO functional class at 3 months and
    regularly thereafter).

# References:

1\. Gaine S. Pulmonary Hypertension. JAMA. 2000;284:3160-8.

2\. Humbert M, Sitbon O, Simonneau G. Treatment of pulmonary
hypertension. N Engl J Med. 2004;351:1425-36.

3\. Simmonneau G, Galie N, Rubin LJ, et al. Clinical classification of
pulmonary hypertension. J Am Coll Cardiol. 2004;43(Suppl 12):5S-12S.

## 4. Letairis™ Product Information. Gilead Sciences, Forest City CA. February 2008.

## 5. Letairis™ Product Dossier. Gilead Sciences, Foster City CA. August 2007.

## 6. Miyamoto S, Nagaya N, Satoh T, et al. Clinical correlates and prognostic significance of six-minute walk test in patients with primary pulmonary hypertension. Am J Respir Crit Care Med. 2000;161:487-92.

7\. Borg GA. Psychophysical bases of perceived exertion. Med Sci Sports
Exerc. 1982;14:377-81.

8\. McGoon M, Gutterman D, Steen V, et al. Screening, early detection,
and diagnosis of pulmonary arterial hypertension. Chest.
2004;126:14S-34S.

9\. Galie N, Olschewski H, Oudiz RJ, et al. Ambrisentan for the
treatment of pulmonary arterial hypertension. Circulation. 2008;117:
(23):3010-9. Epub 2008 May 27.

10\. National Institute for Health and Clinical Excellence (NICE)
Pulmonary Arterial Hypertension (adults) drugs: appraisal consultation
document: *preliminary recommendations*. Accessed at
[www.nice.org.uk/guidance/index.jsp?action=article&o=39688](http://www.nice.org.uk/guidance/index.jsp?action=article&o=39688)
on July 31, 2008.

**Prepared September 2008. Contact person: Lisa Longo, PharmD, BCPS**

# Appendix 1: Clinical Trials

+--------+-------------------------------------------------------------+
| #      | ####### ARIES-1 (AMB-320)                                   |
| ###### |                                                             |
|  Study | Galie et al. Circulation. 2008;117:(23):3010-9              |
|        |                                                             |
|        | Letairis Product Dossier, July 2007.                        |
+--------+-------------------------------------------------------------+
| #      | ## To evaluate                                              |
| ###### | the efficacy and safety of ambrisentan in patients with PAH |
|  Study |                                                             |
|  Goals |                                                             |
+--------+-------------------------------------------------------------+
| ###    | ####### Study Design (n~R~=201)                             |
| #### M |                                                             |
| ethods | -   Phase III, randomized, double-blind,                    |
|        |     placebo-controlled, multi-center trial                  |
|        |                                                             |
|        | -   [Duration]{.underline}: 12 wks                          |
|        |                                                             |
|        | -   [Interventions]{.underline}: ambrisentan 5 mg PO daily; |
|        |     ambrisentan 10 mg PO daily; placebo                     |
|        |                                                             |
|        | -   [Other therapy]{.underline}: supportive therapy         |
|        |     permitted (anticoagulants, oxygen, diuretics, digoxin,  |
|        |     calcium-channel antagonists); other PAH treatments not  |
|        |     permitted                                               |
|        |                                                             |
|        | -   [Primary Endpoint]{.underline}: change from baseline    |
|        |     vs. placebo in the 6MWD                                 |
|        |                                                             |
|        | -   [Secondary Endpoints]{.underline}: TTCW^†^, change from |
|        |     baseline vs. placebo in the WHO Functional Class, SF 36 |
|        |     Health Survey, and BDI                                  |
|        |                                                             |
|        | -   [Safety]{.underline}: adverse events, labs, and vital   |
|        |     signs evaluated                                         |
|        |                                                             |
|        | **Data analysis**                                           |
|        |                                                             |
|        | -   Safety and efficacy analyses were based on intent to    |
|        |     treat (ITT) population. The primary endpoint was        |
|        |     analyzed using the last observation carried forward     |
|        |     (LOCF) when necessary.                                  |
+--------+-------------------------------------------------------------+
| ####   | ####### Inclusion criteria                                  |
| ### Cr |                                                             |
| iteria | -   Aged 18 yrs and older                                   |
|        |                                                             |
|        | -   Diagnosis of IPAH or PAH associated with connective     |
|        |     tissue disease, HIV, or anorexigens                     |
|        |                                                             |
|        | -   6MWD of 150-450 meters                                  |
|        |                                                             |
|        | -   Mean pulmonary artery pressure (mPAP) ≥25 mmHg          |
|        |                                                             |
|        | -   Pulmonary vascular resistance (PVR) \>3 Wood units      |
|        |                                                             |
|        | -   Pulmonary capillary wedge pressure (PCWP) or left       |
|        |     ventricular end diastolic pressure (LVEDP) \<15 mmHg    |
|        |                                                             |
|        | ####### Exclusion criteria                                  |
|        |                                                             |
|        | -   Pregnancy or lactation                                  |
|        |                                                             |
|        | -   Significant restrictive or obstructive lung disease     |
|        |                                                             |
|        | -   Significant LV disease (PCWP or LVEDP ≥15 mmHg)         |
|        |                                                             |
|        | -   Chronic thromboembolic pulmonary hypertension           |
+--------+-------------------------------------------------------------+
| ###    | Baseline Characteristics                                    |
| #### R |                                                             |
| esults | +----------------+------------+------------+------------+   |
|        | |                | *          | **AMB 5    | **AMB 10   |   |
|        | |                | *Placebo** | mg**       | mg**       |   |
|        | |                |            |            |            |   |
|        | |                | (n=67)     | (n=67)     | (n=67)     |   |
|        | +----------------+------------+------------+------------+   |
|        | | \% Male        | 11.9       | 16.4       | 20.9       |   |
|        | +----------------+------------+------------+------------+   |
|        | | \% IPAH        | 64.2       | 62.7       | 61.2       |   |
|        | +----------------+------------+------------+------------+   |
|        | | WHO functional |            |            |            |   |
|        | | class (%)      |            |            |            |   |
|        | +----------------+------------+------------+------------+   |
|        | | I              | 3          | 1.5        | 3          |   |
|        | +----------------+------------+------------+------------+   |
|        | | II             | 34.3       | 29.9       | 33         |   |
|        | +----------------+------------+------------+------------+   |
|        | | III            | 61.2       | 59.7       | 53.7       |   |
|        | +----------------+------------+------------+------------+   |
|        | | IV             | 1.5        | 9          | 10.4       |   |
|        | +----------------+------------+------------+------------+   |
|        | | 6MWD, m, mean  | 341.9      | 339.6      | 340.5      |   |
|        | | (SD)           | (73.5)     | (76.7)     | (77.2)     |   |
|        | +----------------+------------+------------+------------+   |
|        |                                                             |
|        | Results                                                     |
|        |                                                             |
|        | +-------------------------+---------+----+----+---------+   |
|        | |                         | **Pl    | *  |    | **AMB   |   |
|        | |                         | acebo** | *A |    | 10**    |   |
|        | |                         |         | MB |    |         |   |
|        | |                         | (n=67)  | 5  |    | (n=67)  |   |
|        | |                         |         | ** |    |         |   |
|        | |                         |         |    |    |         |   |
|        | |                         |         | (n |    |         |   |
|        | |                         |         | =6 |    |         |   |
|        | |                         |         | 7) |    |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        | | Completed treatment, n  | 57      | 63 |    | 63      |   |
|        | | (%)                     | (85.1)  | (9 |    | (92.6)  |   |
|        | |                         |         | 4) |    |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        | | **Primary Endpoint**    |         |    |    |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        | | Δ 6MWD from baseline to | -7.8    | 22 |    | 43.6    |   |
|        | | wk 12, m, mean (SD)     | (78.9)  | .8 |    | (65.9)  |   |
|        | |                         |         | (8 |    |         |   |
|        | |                         |         | 3) |    |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        | | Relative change vs.     | \-      | 30 |    | 51.4\*  |   |
|        | | placebo, m (95% CI)     |         | .6 |    | (26.    |   |
|        | |                         |         | \* |    | 6,76.2) |   |
|        | |                         |         | (2 |    |         |   |
|        | |                         |         | .9 |    |         |   |
|        | |                         |         | ,5 |    |         |   |
|        | |                         |         | 8. |    |         |   |
|        | |                         |         | 3) |    |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        | | **Secondary Endpoints** | **Pl    |    | *  |         |   |
|        | |                         | acebo** |    | *A |         |   |
|        | |                         |         |    | MB |         |   |
|        | |                         |         |    | 5  |         |   |
|        | |                         |         |    | &  |         |   |
|        | |                         |         |    | 10 |         |   |
|        | |                         |         |    | ** |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        | | Clinical worsening, n   | 6/67    |    | 6  |         |   |
|        | | (%)                     | (9)     |    | /1 |         |   |
|        | |                         |         |    | 34 |         |   |
|        | |                         |         |    | (  |         |   |
|        | |                         |         |    | 4. |         |   |
|        | |                         |         |    | 5) |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        | | TTCW, % event-free at   | 91      |    | 95 |         |   |
|        | | 12 wks                  |         |    | .5 |         |   |
|        | +-------------------------+---------+----+----+---------+   |
|        |                                                             |
|        | \*significant vs. placebo                                   |
|        |                                                             |
|        | **Safety**                                                  |
|        |                                                             |
|        | AE Withdrawals: 3%/3%/3% (Placebo/AMB 5/AMB 10)             |
|        |                                                             |
|        | Deaths: 2/1/1 (Placebo/AMB 5/AMB 10)                        |
|        |                                                             |
|        | Most frequently reported AEs with higher frequency in AMB   |
|        | 5/10 groups: peripheral edema, headache, nasal congestion   |
|        |                                                             |
|        | LFT elevations \>3x ULN: 3%/0/0 (Placebo/AMB 5/AMB 10)      |
+--------+-------------------------------------------------------------+
| #      | In a predominantly female PAH population with primarily WHO |
| ###### | class II/III symptoms, treatment with ambrisentan was       |
|  Concl | associated with significant improvements in exercise        |
| usions | capacity vs. placebo, as measured by 6MWD and secondary     |
|        | indices including TTCW and BDI. Ambrisentan was             |
|        | well-tolerated.                                             |
+--------+-------------------------------------------------------------+
| #      | ####### ARIES-2 (AMB-321)                                   |
| ###### |                                                             |
|  Study | Galie et al. Circulation. 2008;117:(23):3010-9              |
|        |                                                             |
|        | Letairis Product Dossier, July 2007                         |
+--------+-------------------------------------------------------------+
| #      | ## To evaluate                                              |
| ###### | the efficacy and safety of ambrisentan in patients with PAH |
|  Study |                                                             |
|  Goals |                                                             |
+--------+-------------------------------------------------------------+
| ###    | ####### Study Design (n~R~=192)                             |
| #### M |                                                             |
| ethods | -   Phase III, randomized, double-blind,                    |
|        |     placebo-controlled, multi-center trial                  |
|        |                                                             |
|        | -   [Duration]{.underline}: 12 wks                          |
|        |                                                             |
|        | -   [Interventions]{.underline}: ambrisentan 2.5 mg PO      |
|        |     daily; ambrisentan 5 mg PO daily; placebo               |
|        |                                                             |
|        | -   [Other therapy]{.underline}: supportive therapy         |
|        |     permitted (anticoagulants, oxygen, diuretics, digoxin,  |
|        |     calcium-channel antagonists); other PAH treatments not  |
|        |     permitted                                               |
|        |                                                             |
|        | -   [Primary Endpoint]{.underline}: change from baseline    |
|        |     vs. placebo in the 6MWD                                 |
|        |                                                             |
|        | -   [Secondary Endpoints]{.underline}: TTCW^†^, change from |
|        |     baseline vs. placebo in the WHO Functional Class, SF 36 |
|        |     Health Survey, and BDI                                  |
|        |                                                             |
|        | -   [Safety]{.underline}: adverse events, labs, and vital   |
|        |     signs evaluated                                         |
|        |                                                             |
|        | **Data analysis**                                           |
|        |                                                             |
|        | -   Safety and efficacy analyses were based on ITT          |
|        |     population. The primary endpoint was analyzed using the |
|        |     last observation carried forward (LOCF) when necessary. |
+--------+-------------------------------------------------------------+
| ####   | ####### Inclusion criteria                                  |
| ### Cr |                                                             |
| iteria | -   Aged 18 yrs and older                                   |
|        |                                                             |
|        | -   Diagnosis of IPAH or PAH associated with connective     |
|        |     tissue disease, HIV, or anorexigens                     |
|        |                                                             |
|        | -   6MWD of 150-450 meters                                  |
|        |                                                             |
|        | -   PAPm ≥25 mmHg                                           |
|        |                                                             |
|        | -   PVR \>3 Wood units                                      |
|        |                                                             |
|        | -   PCWP or LVEDP \<15 mmHg                                 |
|        |                                                             |
|        | ####### Exclusion criteria                                  |
|        |                                                             |
|        | -   Pregnancy or lactation                                  |
|        |                                                             |
|        | -   Significant restrictive or obstructive lung disease     |
|        |                                                             |
|        | -   Significant LV disease (PCWP or LVEDP ≥15 mmHg)         |
|        |                                                             |
|        | -   Chronic thromboembolic pulmonary hypertension           |
+--------+-------------------------------------------------------------+
| ###    | Baseline Characteristics                                    |
| #### R |                                                             |
| esults | +----------------+------------+------------+------------+   |
|        | |                | *          | **AMB 2.5  | **AMB 5    |   |
|        | |                | *Placebo** | mg**       | mg**       |   |
|        | |                |            |            |            |   |
|        | |                | (n=65)     | (n=64)     | (n=63)     |   |
|        | +----------------+------------+------------+------------+   |
|        | | \% Male        | 32.3       | 25         | 19         |   |
|        | +----------------+------------+------------+------------+   |
|        | | \% IPAH        | 64.6       | 65.6       | 65.1       |   |
|        | +----------------+------------+------------+------------+   |
|        | | WHO functional |            |            |            |   |
|        | | class (%)      |            |            |            |   |
|        | +----------------+------------+------------+------------+   |
|        | | I              | 3.1        | 0          | 1.6        |   |
|        | +----------------+------------+------------+------------+   |
|        | | II             | 36.9       | 53.1       | 44.4       |   |
|        | +----------------+------------+------------+------------+   |
|        | | III            | 56.9       | 45.3       | 52.4       |   |
|        | +----------------+------------+------------+------------+   |
|        | | IV             | 3.1        | 1.6        | 1.6        |   |
|        | +----------------+------------+------------+------------+   |
|        | | 6MWD, m, mean  | 342.7      | 347.3      | 355.3      |   |
|        | | (SD)           | (85.93)    | (83.8)     | (84.5)     |   |
|        | +----------------+------------+------------+------------+   |
|        |                                                             |
|        | Results                                                     |
|        |                                                             |
|        | +------------------------+-------+-----+---+-----------+    |
|        | |                        | *     | **  |   | **AMB 5** |    |
|        | |                        | *Plac | AMB |   |           |    |
|        | |                        | ebo** | 2.  |   | (n=63)    |    |
|        | |                        |       | 5** |   |           |    |
|        | |                        | (     |     |   |           |    |
|        | |                        | n=65) | (n= |   |           |    |
|        | |                        |       | 64) |   |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        | | Completed treatment, n | 83.1  | 9   |   | 92.1      |    |
|        | | (%)                    |       | 0.6 |   |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        | | **Primary Endpoint**   |       |     |   |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        | | Δ 6MWD from baseline   | -10.1 | 2   |   | 49.4      |    |
|        | | to wk 12, m, mean (SD) | (     | 2.2 |   | (75.4)    |    |
|        | |                        | 93.8) | (82 |   |           |    |
|        | |                        |       | .7) |   |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        | | Relative change vs.    | \-    | 32. |   | 59.4\*    |    |
|        | | placebo, m (95% CI)    |       | 3\* |   |           |    |
|        | |                        |       | (   |   | (2        |    |
|        | |                        |       | 1.5 |   | 9.6,89.3) |    |
|        | |                        |       | ,63 |   |           |    |
|        | |                        |       | .1) |   |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        | | **Secondary            | *     |     | * |           |    |
|        | | Endpoints**            | *Plac |     | * |           |    |
|        | |                        | ebo** |     | A |           |    |
|        | |                        |       |     | M |           |    |
|        | |                        |       |     | B |           |    |
|        | |                        |       |     | 2 |           |    |
|        | |                        |       |     | . |           |    |
|        | |                        |       |     | 5 |           |    |
|        | |                        |       |     | & |           |    |
|        | |                        |       |     | 5 |           |    |
|        | |                        |       |     | * |           |    |
|        | |                        |       |     | * |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        | | Clinical worsening, n  | 14/65 |     | 6 |           |    |
|        | | (%)                    | (     |     | / |           |    |
|        | |                        | 21.5) |     | 1 |           |    |
|        | |                        |       |     | 2 |           |    |
|        | |                        |       |     | 7 |           |    |
|        | |                        |       |     | ( |           |    |
|        | |                        |       |     | 4 |           |    |
|        | |                        |       |     | . |           |    |
|        | |                        |       |     | 7 |           |    |
|        | |                        |       |     | ) |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        | | TTCW, % event-free at  | 78.5  |     | 9 |           |    |
|        | | 12 wks                 |       |     | 5 |           |    |
|        | |                        |       |     | . |           |    |
|        | |                        |       |     | 3 |           |    |
|        | |                        |       |     | \ |           |    |
|        | |                        |       |     | * |           |    |
|        | +------------------------+-------+-----+---+-----------+    |
|        |                                                             |
|        | \*significant vs. placebo                                   |
|        |                                                             |
|        | **Safety**                                                  |
|        |                                                             |
|        | AE Withdrawals: 4.6%/1.6%/4.8% (Placebo/AMB 2.5/AMB 5)      |
|        |                                                             |
|        | Deaths: 4/2/0 (Placebo/AMB 2.5/AMB 5)                       |
|        |                                                             |
|        | Most frequently reported AEs occurring more frequently in   |
|        | AMB 2.5/5 groups: headache, palpitations, flushing,         |
|        | insomnia, dyspnea, abdominal pain, nasal congestion         |
|        |                                                             |
|        | LFT elevations \>3x ULN: 1.5%/0/0 (Placebo/AMB 2.5/AMB 5)   |
+--------+-------------------------------------------------------------+
| #      | In a predominantly female PAH population with primarily WHO |
| ###### | class II/III symptoms, treatment with ambrisentan was       |
|  Concl | associated with significant improvements in exercise        |
| usions | capacity vs. placebo, as measured by 6MWD and secondary     |
|        | indices including TTCW and BDI. Ambrisentan was             |
|        | well-tolerated.                                             |
+--------+-------------------------------------------------------------+

^†^TTCW=death, lung transplant, hospitalization for PAH, atrial
septostomy, study withdrawal due to addition of PAH drugs, or early
escape. Early escape criteria allowed patients to prematurely
discontinue the study due to lack of efficacy.