Phase 2 Study to Assess Safety, Tolerability and Efficacy of Once Weekly SC PB1046 in Subjects With Symptomatic PAH

Conditions:High Blood Pressure (Hypertension)
Therapuetic Areas:Cardiology / Vascular Diseases
Age Range:18 - 79
Start Date:July 15, 2018
End Date:January 31, 2020

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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.

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 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 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 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 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.

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

- 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

- 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.

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 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.
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