ABI-009, an mTOR Inhibitor, for Patients With Severe Pulmonary Arterial Hypertension

Inclusion Criteria:

- Male or female age >18 year old with a current diagnosis of WHO Group 1 PAH including
idiopathic pulmonary arterial hypertension (IPAH), heritable pulmonary arterial
hypertension (HPAH), drug and toxin induced PAH, or PAH associated with connective
tissue disease, or congenital heart defects (repaired greater than 1 year prior to
Screening)

- Must meet following hemodynamic definition prior to initiation of study drug

- Mean PAP of ≥ 25 mm Hg

- PCWP or left ventricular end diastolic pressure (LVEDP) of ≤ 12 mm

- PVR >5 mmHg/L/min (Woods unit)

- Functional class III or IV according to the WHO set forth at the Dana Point
Classification 2008 Meeting

- On 2 or more specific standard PAH therapies (for ≥ 12 consecutive weeks and at stable
dose for ≥ 8 consecutive weeks) unless documented inability to tolerate 2 standard
therapies

- Meet the following criteria determined by pulmonary function tests completed no more
than 24 weeks prior to screening, performed with or without bronchodilation:

- Forced expiratory volume in one second (FEV1) ≥ 55% of predicted normal

- FEV1:forced vital capacity (FVC) ratio ≥ 0.60

- 6MWD ≥150 meters and ≤450 meters

- Negative serum pregnancy test

- Female of childbearing age either surgically sterilized or using acceptable method of
contraception

- Ability to provide written informed consent by the patient or legal guardian

Exclusion criteria:

- History of heart disease including left ventricular ejection fraction (LVEF) ≤ 40% or
clinically significant valvular constrictive or atherosclerotic heart disease
(myocardial infarction, angina, cerebrovascular accident)

- History of malignancy in 2 years prior to enrollment

- Pulmonary hypertension (PH) belonging to groups 2 to 5 of the 2013 Nice classification

- Current or recent (< 3 months) use of inotropic or vasopressor agents for the
treatment of PAH

- Recent (< 3 months) PAH related hospital admission

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition including macrolide (eg, azithromycin, clarithromycin, dirithromycin, and
erythromycin) and ketolide antibiotics

- Uncontrolled diabetes mellitus as defined by HbA1c >8% despite adequate therapy

- Uncontrolled hyperlipidemia (serum triglyceride ≥300 mg/dL)

- Serum cholesterol ≥350 mg/dL

- Surgery within 3 months of start date of study drug

- Baseline cytopenias:

- Absolute Neutrophil Count ≤ 1.5 x 109/L

- Hemoglobin ≤ 9 g/dL

- Platelet count < 100,000/mm3

- Baseline liver disease: ALT/AST, total bilirubin, alkaline phosphatase >1.5 x ULN

- Baseline renal disease: creatinine >1.5 ULN and/or creatinine clearance (Cockroft
formula) ≤ 60 mL/min

- Inability to attend scheduled clinic visits

- Prior use of study drug within previous 6 months from enrollment

- Previous lung transplant

- Naïve to available standard PAH therapy

- Concomitant genetic or acquired immunosuppressive diseases (such as HIV, AIDS)

- Uncontrolled intercurrent illness that in the opinion of the investigator would limit
compliance and tolerance to study requirements (eg, ongoing or active infection,
symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia,
diabetes, uncontrolled hypertension, coronary artery disease, or psychiatric
illness/social situations)

- Concomitant enrollment in another investigational treatment protocol for PAH

- Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving
the first dose of ABI-009. Additionally, use of any known CYP3A4 substrates with
narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride,
dihydroergotamine, pimozide, quinidine, terfanide) within the 14 days prior to
receiving the first dose of ABI-009