Phase 2 Study to Assess Safety, Tolerability and Efficacy of Once Weekly SC Pemziviptadil (PB1046) in Subjects With Symptomatic PAH
Phase 2 Study to Assess Safety, Tolerability and Efficacy of Once Weekly SC Pemziviptadil (PB1046) in Subjects With Symptomatic PAH
This is a multi-center, randomized, double-blind, controlled, Phase 2 study to assess the
 safety, tolerability, and efficacy of pemziviptadil (PB1046) at the optimally titrated dose
 after 16 weeks of treatment. Subjects will be randomized in a 2:1 ratio to one of two
 parallel dose groups: a) high-dose group where PB1046 will be up-titrated from a 0.2 mg/kg
 minimally effective starting dose to a target high dose level of at least 1.2 mg/kg or higher
 to a maximally tolerated dose (MTD), or b) a low-dose group that will start at 0.2 mg/kg and
 remain at this minimally effective dose (MED) level with sham up-titration. The total
 treatment period will be comprised of 2 phases: 1) an initial 10 week dose titration phase in
 which weekly doses of PB1046 will be titrated (or sham titrated) up to a target dose level of
 at least 1.2 mg/kg or higher to the MTD, and 2) a maintenance of treatment phase that begins
 when subjects reach week 11 and continues for 6 weeks during which no further up-titration
 should occur.
The primary safety and tolerability objectives will be assessed by investigating the
 incidence and severity of adverse events (AEs) as well as changes from baseline in vital
 signs, laboratory parameters, ECGs and their relationship to pemziviptadil (PB1046). The
 primary efficacy objective will be assessed by investigating the change in PVR derived from
 right heart catheterization (RHC). Secondary efficacy objectives will be assessed by
 investigating the impact of pemziviptadil (PB1046) on change from baseline in 6 minute walk
 distance (6MWD) test and NT-proBNP, a prognostic biomarker for PAH, in the two groups
 (comparing the MTD and MED groups) at the end of the treatment period. In addition, the
 effect of pemziviptadil (PB1046) on other cardiopulmonary hemodynamic parameters (e.g. CI,
 mPAP, mRAP, wedge pressure and SvO2) as measured by RHC will be assessed. Changes in BDI,
 HRQoL, and NYHA/WHO (New York Heart Association/World Health Organization) FC will also be
 assessed.

 An independent Data Safety Monitoring Board (DSMB) will periodically assess safety, efficacy
 and biomarker data to independently assess the overall safety profile of pemziviptadil
 (PB1046), to help adjudicate potential dose-limiting toxicities, and to monitor the overall
 benefit risk profile of pemziviptadil (PB1046) during the study. The DSMB will review the
 safety and tolerability data after the first 10 subjects while recruitment is ongoing.
Inclusion Criteria:

 -  Male and female subjects with PAH, ≥18 and ≤ 79 years of age, who are symptomatic and
 have reduced exercise capacity due primarily to their PAH diagnosis and have been
 assessed by a qualified individual (i.e. physician, physician assistant, nurse
 practitioner) to be in NYHA/WHO functional class II or III;

 -  Willing and able to sign a written informed consent prior to all study-related
 procedures;

 -  Subjects with PAH belonging to one of the following subgroups of the Nice Clinical
 Classification of Pulmonary Hypertension Group 1: a. Idiopathic, b. Heritable, c. Drug
 or toxin-induced, d. Associated with connective tissue disease, HIV infection, portal
 hypertension, congenital heart disease (pulmonary-to-systemic shunt;

 -  Two 6MWD test results > 50 m and < 550 m prior to randomization with results +/- 10%
 of each other. Note: Up to four tests may be conducted between Screening and
 Randomization for eligibility purposes;

 -  Hemodynamic assessment of PAH demonstrating elevated mPAP and PVR as indicated below
 during the Screening Period: a. mean pulmonary artery pressure (mPAP) of ≥ 25 mmHg;
 and, b. pulmonary vascular resistance (PVR) ≥ 400 dyne•sec/cm5; and, c. pulmonary
 capillary wedge pressure (PCWP) or left ventricular end diastolic pressure (LVEDP) of
 ≤ 12 mmHg if PVR ≥ 400 and < 500 dynes•sec/cm5; or PCWP/LVEDP ≤ 15 mmHg if PVR ≥ 500
 dynes•sec/cm5;

 -  Body mass index ≥ 18 kg/m2 and ≤ 40 kg/m2 at screening;

 -  Meet the following criteria determined by pulmonary function tests completed no more
 than 24 weeks prior to screening: a. Forced expiratory volume in one second (FEV1) ≥
 55% of predicted normal, b. FEV1: FVC (forced vital capacity) ratio ≥ 0.60;

 -  Agrees to use a medically acceptable method of contraception (both male and female
 patients) throughout the entire study period and continuing for 30 days after their
 last dose of study drug;

 -  Stable background medical regimen of up to 3 oral PAH therapies for at least 30 days
 prior to Screening and having been on PAH therapy for at least 3 months;

 -  If a subject has historical diagnosis (prior to screening visit) of being positive for
 human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis
 C virus (HCV), must be clinically stable and if on therapy, must be on stable therapy
 for HIV or HCV for at least 3 months; Willing and able to understand and follow
 instructions; return to the study unit for specified study visits; and able to
 participate in the study for the entire period.

 Exclusion Criteria:

 -  Concomitant medical disorder, condition, or history, that in the opinion of the
 Investigator would impair the subject's ability to participate in or complete the
 requirements of the study;

 -  Concomitant medical disorder that is expected to limit the subject's life-expectancy
 to ≤ 1 year;

 -  Pregnant or lactating female subjects;

 -  First positive result from serology testing at visit 1 (screening labs) for HIV,
 HBsAg, or HCV prior to randomization;

 -  Participation in another investigational drug study within 30 days prior to screening
 or participating in a non-medication study which, in the opinion of the Investigator,
 would interfere with the study compliance or outcome assessments;

 -  Use of chronic subcutaneous prostanoid/prostacyclin therapy for PAH within 30 days
 prior to screening, including prostacyclin receptor agonists;

 -  More than mild mitral or aortic valve disease, left ventricular ejection fraction <
 50%, or left ventricular regional wall motion abnormality suggestive of active
 coronary artery disease on documented 2D-echocardiography occurring within 12 months
 of Screening;

 -  Sustained systolic blood pressure (SBP) < 95 mmHg and/or diastolic blood pressure
 (DBP) < 50 mmHg (confirmed by a duplicate seated reading) on at least 3 consecutive
 readings (self-monitored or office) at screening and prior to dosing, or overt
 symptomatic hypotension;

 -  Sustained resting heart rate >110 beats per minute (BPM) (confirmed by duplicate
 assessments of office vital signs or consecutive ECG assessments) on at least 3
 consecutive readings at screening and prior to dosing;

 -  Clinically significant renal dysfunction at the Screening Visit as measured by the
 estimated glomerular filtration rate (eGFR)

 -  Significant liver dysfunction as measured by any one of the following at screening: a.
 alanine aminotransferase (ALT) >3.0 times upper limit of normal (ULN) or; b. aspartate
 aminotransferase (AST) >3.0 times ULN or; c. serum bilirubin ≥ 1.6 mg/dL;

 -  Known history of substance abuse within the past 1 year that in the opinion of the
 Investigator would impair the subject's ability to participate in or complete the
 requirements of the study;

 -  Any major surgical procedure within 90 days prior to screening or planned surgical
 procedure during the study period;

 -  Any in-patient hospitalization (defined as greater than 23 hours) within 30 days of
 subject screening;

 -  Enrollment within the past 3 months prior to screening or plans to enroll during the
 study into a cardiopulmonary rehabilitation program;

 -  Other medical or psychiatric condition which, in the opinion of the Investigator,
 would place the subject at increased risk or would preclude obtaining voluntary
 consent or would confound the objectives of study;

 -  Known hypersensitivity to study drug or any of the excipients of the drug formulation;

 -  More than two of the following: a. BMI > 35; b. Current atrial fibrillation; c.
 Current Diabetes Mellitus; d. Current hypertension; e. History of clinically
 significant coronary artery disease in prior 3 years.