A Randomized, Double-Blind, Parallel Group, Phase 2 Study to Assess the Safety, Tolerability, and Efficacy of Once Weekly Subcutaneous (SC) Injections of a Sustained-Release Vasoactive Intestinal Peptide (VIP) Analogue, PB1046, in Adult Subjects With Symptomatic Pulmonary Arterial Hypertension (PAH)
This is a multi-center, randomized, double-blind, controlled, Phase 2 study to assess the safety, tolerability, and efficacy of 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.
An independent Data Safety Monitoring Board (DSMB) will periodically assess safety, efficacy and biomarker data to independently assess the overall safety profile of PB1046, to help adjudicate potential dose-limiting toxicities, and to monitor the overall benefit risk profile of PB1046 during the study. The DSMB will review the safety and tolerability data after the first 10 subjects while recruitment is ongoing.
18 Years to 79 Years
Accepting Healthy Volunteers?
- 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, e.g., atrial septal defect (ASD) or patent ductus arteriosus (PDA), at least 1 year after surgical repair);
- Two 6MWD test results > 50 m and < 525 m prior to dosing with results +/- 10% of each other. Note: Up to four tests may be conducted between Screening and Baseline for eligibility purposes (no more than two 6MWD tests may be performed on the same day, and must be completed at least two hours apart);
- Hemodynamic assessment of PAH by right heart catheterization (RHC) 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;
- Male subjects and female subjects of childbearing potential willing and able to practice effective contraception during the study and continuing contraception for 30 days after their last dose of study drug. Female subjects of non-childbearing potential are defined as being surgically sterile by bilateral tubal ligation, bilateral oophorectomy, or hysterectomy. A female subject 45 to 60 year of age, inclusive who is post-menopausal for at least 1 year and has a follicle-stimulating hormone level confirmation indicating post-menopausal status will be considered of non-childbearing potential. Female subjects >60 years of age are considered post-menopausal and of non-childbearing potential;
- Stable background medical regimen of up to 2 oral PAH therapies for at least 30 days prior to Screening and having been on PAH therapy for at least 4 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.
- 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 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) of < 40 mL/min/1.73m2 as calculated by the MDRD equation: eGFR = 186 x (Creat / 88.4)-1.154 x (Age)-0.203 x (0.742 if female) x (1.210 if black)
- 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.