Long-term Ambrisentan Extension Study for Pediatric Patients Who Participated in AMB112529

Pulmonary arterial hypertension (PAH) is a rare, progressive, highly debilitating disease
characterized by vascular obstruction and the variable presence of vasoconstriction, leading
to increased pulmonary vascular resistance and right-sided heart failure. If left untreated,
PAH ultimately leads to right ventricular failure and death; adult subjects have a median
survival of 2.8 years without treatment. Epidemiological estimates vary but prevalence in
Europe is thought to be of the order of 15 cases per million. Large scale epidemiology
studies of PAH in children have not been conducted and there is no or limited outcome data in
paediatric PAH patients. A register in France (1995-1996) estimates the prevalence in
children is as low as 3.7 cases per million. In a national, comprehensive country wide survey
of the epidemiology of idiopathic PAH (IPAH) management and survival in the United Kingdom
(UK) the incidence was 0.48 cases per million children per year and the prevalence was 2.1
cases per million children.

Ambrisentan (VOLIBRIS™ tablets) is an endothelin receptor antagonist (ERA) marketed in the
European Union (EU) and some other countries by GlaxoSmithKline (GSK) and in the United
States as LETAIRIS® by Gilead Sciences Inc. Ambrisentan is indicated for the treatment of
adult patients with PAH to improve exercise capacity, decrease the symptoms of PAH, and delay
clinical worsening.

The primary purpose of this long term paediatric study is to provide clinically relevant
information on the long term safety of ambrisentan in children with the most common causes of
PAH in this age group. This study is only open to patients who have participated in Study
AMB112529, A randomized, open label study comparing safety and efficacy parameters for a high
and a low dose of ambrisentan (adjusted for body weight) for the treatment of pulmonary
arterial hypertension in paediatric patients aged 8 years up to 18 years, and in whom
continued treatment with ambrisentan is warranted.

This study is part of a Paediatric Investigational Plan (PIP; EMEA-000434-PIP01-08) agreed
with the European Medicines Agency's Paediatric Committee (PDCO).

Inclusion Criteria:

- Have participated in and complied, to the best of their ability, with the protocol for
AMB112529 and have met one of the following:

1. Completed the Week 24 visit in AMB112529;

2. Required additional targeted treatment for PAH due to inadequate response to the
current treatment or worsening of their clinical condition prior to week 24 in
AMB112529;

3. Required reduction in dose of baseline targeted treatment for PAH after
ambrisentan was added to the treatment regimen;

4. In the opinion of the investigator, continued treatment with ambrisentan is
warranted.

- A female is eligible to participate in this study, as assessed by the investigator, if
she is of:

1. Non-childbearing potential (i.e., physiologically incapable of becoming
pregnant); or,

2. Child-bearing potential - has a negative pregnancy test and is not lactating and,
if sexually active, agrees to continue to use 2 reliable methods of contraception
until study completion and for at least 30 days following the last dose of study
drug (reliable methods of contraception are listed in Appendix 2).

- Subject or subject's legal guardian is able and willing to give written informed
consent. As part of the consent, female subjects of childbearing potential will be
informed of the risk of teratogenicity and will need to be counselled in a
developmentally appropriate manner on the importance of pregnancy prevention; and male
subjects will need to be informed of potential risk of testicular tubular atrophy and
aspermia.

Exclusion Criteria:

- Subjects who were withdrawn from ambrisentan in Study AMB112529;

- Subjects who did not comply with the protocol in Study AMB112529;

- Female subjects who are pregnant or breastfeeding;

- Subjects with severe renal impairment (estimated creatinine clearance <30 mL/min
assessed within the previous 45 days) at the point of transition from Study AMB112529
into this study;

- Subject with clinically significant fluid retention in the opinion of the
investigator;

- Subject with clinically significant anaemia in the opinion of the investigator;

- Subjects who are to enter another clinical trial or be treated with another
investigational product after exiting Study AMB112529.