Novel Evaluation With QGC001 in Hypertensive Overweight Patients of Multiple Ethnic Origins
Novel Evaluation With QGC001 in Hypertensive Overweight Patients of Multiple Ethnic Origins
Essential hypertension (HTN) is a disease that affects approximately 1 billion individuals
 worldwide. Despite the availability of effective and safe anti-hypertensive drugs, 65% of
 subjects diagnosed with HTN do not have their blood pressure (BP) controlled (<140/90 mmHg).
 The overall incidence of resistant HTN, (defined as requiring 3 or more anti-hypertensive
 drugs, including a diuretic, to control BP) is estimated to be 15% of the hypertensive
 population. Consequently, there is a pressing unmet medical need to develop new classes of
 anti-hypertensive drugs that act on alternative pathways and further control BP and the
 associated cardiovascular risks in subjects.

 The prevalence of HTN in African Americans in the United States is among the highest in the
 world, and HTN is more common in African Americans than in Caucasians. One of the risk
 factors for HTN is sodium sensitivity. There is a higher association of HTN with sodium
 sensitivity in African American subjects and other racial/ethnic groups who are
 overweight/obese.

 Effective agents to treat HTN in this high-risk population are clearly needed.

 This study will be conducted in a hypertensive, overweight subject population of multiple
 ethnic origins in which QGC001 is likely, based on its mode of action, to demonstrate a
 significant anti-hypertensive effect.
QGC001 is a prodrug of the specific and selective APA inhibitor, EC33, and is the prototype
 of a new class of centrally-acting anti-hypertensive agents called brain APA inhibitors.
 Inhibition of brain APA, which converts Ang II into Ang III, has emerged as a novel anti
 hypertensive treatment, as demonstrated in several experimental animal models. QGC001's
 anti-hypertensive effect is in part due to: 1) a decrease in arginine vasopressin release in
 the blood circulation, increasing diuresis, which reduces the size of body fluid compartment;
 and 2) a reduction in the sympathetic tone, leading to subsequent decreases in vascular
 resistances.

 This study is an open-label, dose-titrating safety and efficacy study of QGC001 administered
 PO, BID, over 8 weeks in hypertensive overweight subjects of multiple ethnic and racial
 groups in the United States.

 The primary objective of this study is to assess the effects of twice daily (BID)
 administration of oral (PO) QGC001 (250 mg BID, 500 mg BID, and 500 mg BID +
 hydrochlorothiazide (HCTZ) 25 mg once daily [QD]) on blood pressure (BP) over 8 weeks in
 hypertensive overweight/obese subjects of multiple races/ethnicities.
Inclusion Criteria:

 -  Subject must provide signed written informed consent;

 -  Men and women greater than or equal to 18 years of age at Screening;

 -  Diagnosis of primary (essential) hypertension (HTN) for at least 3 months prior to
 Screening and have an office SBP:

 -  Between 145 mmHg and 170 mmHg at Screening and are treatment-naïve; or

 -  Between 130 mmHg and 150 mmHg at Screening and are treated with less than or
 equal to 2 anti hypertensive medications. Anti-hypertensive medications must be
 stable for greater than or equal to 8 weeks prior to Screening;

 -  SBP between 145 mmHg and 170 mmHg, inclusive, and DBP less than or equal to 105 mmHg
 at the Inclusion Visit after 2-week Run In Period;

 -  Body mass index between 25 kg/m2 and 45 kg/m2 with the ability to fit the ambulatory
 blood pressure monitoring (ABPM) cuff per the manufacturer;

 -  Subject must have a successful ABPM measurement prior to receiving the study drug.

 -  Women of childbearing potential and non-surgically sterile male subjects who are
 sexually active must agree to use an approved highly effective form of contraception
 from the time of informed consent until 30 days post-dose.

 -  Women of childbearing potential must have a negative serum pregnancy test result at
 Screening and a negative urine pregnancy test result at the Inclusion Visit (Day 0).

 Exclusion Criteria:

 -  Known or suspected secondary HTN (eg, renal artery stenosis, pheochromocytoma,
 Cushing's disease);

 -  Office SBP greater than or equal to 171 mmHg and/or office diastolic blood pressure
 (DBP) greater than or equal to 105 mmHg at the Inclusion Visit (Day 0) and confirmed
 by a second measurement (not on the same day), preferably within 1 day;

 -  Known hypertensive retinopathy (Keith-Wagener Grade 3 or Grade 4) and/or hypertensive
 encephalopathy;

 -  History of spontaneous or drug-induced angioedema;

 -  Clinically significant valvular heart disease or severe aortic stenosis;

 -  Subjects with symptomatic heart failure (New York Heart Association Class II to Class
 IV);

 -  History of acute coronary syndrome (non-ST elevation myocardial infarction, ST
 elevation myocardial infarction, and unstable angina pectoris), stroke, or transient
 ischemic attack within 6 months prior to Screening;

 -  Known history of malabsorption syndrome, or has undergone gastrointestinal surgery,
 including bariatric procedures, that induce chronic malabsorption, within 2 years of
 Screening;

 -  Treatment with anti-obesity drugs or procedures 3 months prior to Screening (ie,
 surgery, aggressive diet regimen, etc.), leading to unstable body weight;

 -  Female who is breast feeding, pregnant, or planning to become pregnant during the
 study period;

 -  Medical history of cancer (except for basal cell carcinoma) and/or treatment for
 cancer within the last 5 years;

 -  Subject with an upper arm circumference that exceeds the upper circumference level
 (48.3 cm) of the cuff size of either the ABPM and/or office BP (OBP) measurement
 device used in the study;

 -  Night shift workers who routinely sleep during the daytime and/or whose work hours
 include midnight;

 -  Alanine aminotransferase, aspartate aminotransferase, or alkaline phosphatase >3 x
 upper limit of normal (ULN) or a total bilirubin greater than or equal to 2 x ULN
 (unless secondary to Gilbert's syndrome) at Screening or the Inclusion Visit (Day 0);

 -  Estimated glomerular filtration rate <45mL/min/1.73m2, as calculated using the Chronic
 Kidney Disease Epidemiology Collaboration formula at Screening or the Inclusion Visit
 (Day 0);

 -  History of any blood disorder, other than sickle cell trait, causing hemolysis or
 unstable red blood cells (eg, malaria, babesiosis, hemolytic anemia, thalassemia,
 sickle cell anemia);

 -  Subjects with type 1 diabetes mellitus;

 -  Subjects with type 2 diabetes mellitus who:

 -  Are poorly controlled, defined as hemoglobin A1c >8% at Screening; or

 -  Are taking short-acting insulin or sodium-glucose co transporter 2 inhibitors.
 Use of a stable dose (greater than or equal to 12 weeks prior to Screening) of
 medications listed in Appendix C is permitted;

 -  Routine or anticipated treatment with all systemic corticosteroids. Use of topical,
 inhaled, or nasal corticosteroids is permitted;

 -  Clinical evidence of thyroid disease, thyroid hormone therapy that is not stable
 greater than or equal to 4 weeks prior to Screening, or subjects with the following
 thyroid-stimulating hormone (TSH) levels at Screening:

 -  For subjects on replacement therapy: TSH 0.75 to 1.5 x ULN; or

 -  For subjects not on replacement therapy: TSH >1.5 x ULN;

 -  History of alcohol or drug abuse within the 3 months prior to Screening that would
 interfere with study participation or lead to decreased compliance to study procedures
 or study drug intake in the Investigator's opinion;

 -  Participation in another clinical study involving an investigational drug within 30
 days prior to Screening, or plans to participate in another clinical study within 30
 days of discontinuation of study drug;

 -  Any condition, in the opinion of the Investigator, that would interfere with study
 participation, may pose a risk to the subject, or would make study participation not
 in the best interest of the subject;

 -  Subjects with a life expectancy of less than 1 year per Investigator's discretion; or

 -  Any subject who, in the opinion of the Investigator, will not be able to follow the
 protocol.