Efficacy and Safety of Ambrisentan in Children 8-18yrs

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
pediatric 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 paediatric study is to provide clinically relevant information on
the safety and pharmacokinetic profile of ambrisentan in children with the most common causes
of PAH in this age group. The design of the study is also intended to provide information to
guide dose selection and supportive efficacy data in this age group. Despite the fact that
none of the currently available adult treatments are licensed for use in children <12 yrs,
(with the exception of bosentan which was recently approved for use in paediatric population
from 2 years of age) they are widely used off label. This study will provide useful
prescribing information to the medical community for treating this orphan disease in children
in this environment of rapidly changing medical practice.

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:

- Current diagnosis of PAH (WHO Group 1) with WHO class II or III symptoms in one of the
following categories: Idiopathic, Heritable [familial], Secondary to connective tissue
disease (e.g., limited scleroderma, diffuse scleroderma, mixed connective tissue
disease (CTD), systemic lupus erythematosus, or overlap syndrome), or Persistent PAH
despite surgical repair (at least 6 months prior to the screening visit) of atrial
septal defects, ventricular septal defects, atrio-ventricular septal defects, and
persistent patent ductus.

- Have met the following hemodynamic criteria for subjects with right heart
catheterization (RHC) when performed as part of the diagnosis or routine care: mean
pulmonary arterial pressure (mPAP) of >/=25 mmHg, pulmonary vascular resistance (PVR)
of >/=240 dyne sec/cm5, left ventricular end diastolic pressure (LEVDP) or pulmonary
capillary wedge pressure (PCWP) of ≤15 mmHg.

- be treatment naïve, have discontinued treatment with another ERA (e.g., bosentan) at
least 1 month previously because of elevated liver function tests (LFTs), or have been
on a stable dose of drug therapy for PAH (e.g., sildenafil or prostacyclin) for at
least one month prior to the Screening Visit.

- Subjects who discontinued ERA treatment due to elevated LFTs, must have LFTs of <3 x
Upper Limit of Normal (ULN).

- A female is eligible to participate in this study, as assessed by the investigator, if
she is of: a. non-childbearing potential (i.e., physiologically incapable of becoming
pregnant); or, b. Child-bearing potential - has a negative pregnancy test and is not
lactating at the Screening and Baseline/Randomisation Visits and, if sexually active,
agrees to use 2 reliable methods of contraception from the Screening Visit until study
completion and for at least 30 days following the last dose of study drug.

- 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:

- currently taking an ERA.

- currently taking cyclosporine A.

- body weight is less than 20 Kg.

- have not tolerated PAH therapy due to adverse effects which may be related to their
mechanism of action (e.g., prostanoids, ERA, PDE-5 inhibitors) with the exception of
liver abnormalities for those subjects who were receiving another ERA.

- pregnant or breastfeeding.

- diagnosis of active hepatitis (hepatitis B surface antigen and hepatitis C antibody),
or clinically significant hepatic enzyme elevation (i.e., ALT, AST or AP >3xULN) at
Screening.

- severe renal impairment (creatinine clearance <30 mL/min) at Screening.

- clinically significant fluid retention in the opinion of the investigator.

- clinically significant anaemia in the opinion of the investigator.

- a known hypersensitivity to the study drug, the metabolites, or formulation
excipients.

- have participated in another trial or have taken another investigational product
during the previous 30 days.

- alcohol abuse, illicit drug use within 1 year.

- any concurrent condition or concurrent use of medication that would affect subject
safety in the opinion of the investigator.