mTOR activation has been shown to be relevant in the development and progression of pulmonary hypertension. Inhibition of mTOR has been shown to reverse or regress pulmonary hypertension in animal models. nab-Sirolimus (also known as ABI-009, nab-rapamycin) is an albumin-bound mTOR inhibitor with improved penetration in lung tissue.

nab-Sirolimus, an mTOR inhibitor, is a novel formulation of albumin-bound sirolimus nanoparticles and has produced encouraging results in oncology at doses up to 100 mg/m2 given once weekly IV. This study is aimed to determine the optimal clinial dose of once weekly IV nab-sirolimus in patients with PAH and safety of 16 weeks of therapy (Phase 1, Dose finding Safety Part) followed optionally by up to 32 weeks of therapy (Extension Part).

Inclusion Criteria:

• Male or female age >18 years 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 ≤ 15 mm
  • PVR > 5 mmHg/L/min (Woods unit)

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

• On 2 or more specific standard PAH therapies (for ≥ 8 consecutive weeks and at stable dose for ≥ 4 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 (< 2 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 (Cockcroft formula) ≤ 30 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

The safety analysis set includes all treated patients

Adverse Events reported in the initial 16-Week Treatment for all Cohorts 1,2,3,4 & 5 (ie, from baseline through Week 16). Adverse Events reported in the Optional Extension Phase for up to additional 32 weeks of treatment for Cohorts 2, 3, 4, and 5 (ie, Week 17 through 48).

The originally planned dose levels started at 10 mg/m2 weekly nab-sirolimus. While there were no DLTs at the initial dose level (n = 4), based on the totality of AEs and dose reductions, dose levels were modified and patients sequentially enrolled at 1.0, 2.5, 5.0, and 7.5 mg/m2. Given the difficulties with enrollment during the COVID-19 pandemic, the study closed prior to fully enrolling at the last dose level of 7.5 mg/m2 and thus, no Phase 1b cohort expansion occurred at this dose.