A phase I/IIa study to assess safety, tolerability, pharmacokinetic, pharmacodynamic effects and exploratory efficacy of two doses of AGMG0201 in patients with essential hypertension.

Exclusion Criteria34

• Participants with any of the following criteria will not be eligible for participation in this study:
• Participants who have been using two or more antihypertensive medications, excluding the combination of ACEi plus CCB, ACEi plus diuretic, ARB plus CCB or ARB plus diuretic, prior to the first screening visit (Screen1)
• Participants unable to safely discontinue antihypertensive medications for a minimum of 4.5 months, as required by protocol
• Severe hypertension at screening, defined as mean SBP greater than or equal to 180 mmHg OR mean DBP greater than or equal to 110 mmHg
• Orthostatic hypotension, defined as a decrease in mean SBP of greater than or equal to 15 mmHg within three minutes of standing when compared with blood pressure from the semi-supine position at screening (assessed at the second screening visit (Screen2) if volunteer on antihypertensive medication at the first screening visit (Screen1))
• Any history of intolerance to dihydropyridine CCBs
• Any history of intolerance to ACE inhibitors or Angiotensin II antagonists
• Participants of African descent, defined as having both parents identifying themselves as being of African origin
• Renal insufficiency, defined as Creatinine Clearance less than or equal to 40 ml per min, as determined by the Cockcroft Gault equation at screening (assessed at the second screening visit (Screen2) if volunteer on antihypertensive medication at the first screening visit (Screen1))
• Serum potassium greater than upper limit of normal (ULN) at Screening (assessed at the Screen2 visit if volunteer on antihypertensive medication at Screen1; if the volunteer was taking ARBs at the Screen1 and potassium level is still elevated at Screen2, the participant may be re-screened 2 weeks later)
• Proteinuria or hematuria with urine dipstick greater than or equal to 2+ protein or greater than or equal to 1+ blood at screening or at any time within the 6 months prior to screening (assessed at the second screening visit (Screen2) if volunteer on antihypertensive medication at the first screening visit (Screen1))
• Participants with secondary hypertension
• Participants with mental health conditions requiring current pharmacological treatment
• History of macrovascular complications resulting from type II diabetes mellitus or poorly controlled diabetes as evidenced by a haemoglobin A1c (HbA1c) greater than or equal to 8.5 % at screening.
• AST greater than 3 times ULN and/or ALT greater than 3 times ULN at screening
• History or presence of allergic symptoms such as bronchial asthma (within past three months), or drug-induced immediate hypersensitivity
• History or presence of malignancy, HIV, hepatitis (B or C), syphilis, immunosuppressive disease or clinically significant autoimmune disease which may affect the participant’s normal immune response. Treated basal cell or squamous cell carcinoma of the skin, or low grade cancers that are stable and not interfering with exercise may be allowed with permission from the Medical Monitor
• Presence of any clinically significant central nervous system disease associated with persistent neurological abnormalities.
• Presence or history of any ischaemic heart disease, arrhythmias, or cerebrovascular disease
• Family history (1st degree family member) of sudden death of collapse indicative of long QT syndrome
• QTcF greater than or equal to 450 milliseconds at screening
• Participants on medications that could affect blood pressure, e.g. continued use of COX-2 inhibitors and NSAIDS for pain management, that are unable to safely discontinue these medications for the study period
• Presence of any chronic condition which has been unstable or associated with medication changes for these conditions within the 4 weeks prior to screening
• Systemic (oral or injected) steroid use in the last 3 months, or the presence of a condition which may result in systemic steroid use (e.g. asthma, gout, chronic obstructive airways disease) for the month after initial and booster vaccination
• Any history of hypersensitivity after administration of any vaccines, and allergic, including anaphylactic, reactions to any vaccines
• Participation in another clinical study involving the administration of an investigational drug within 12 weeks or 5 half-lives of the planned date of first vaccination, whichever is the longest
• Donation or collection of greater than or equal to 400 mL of blood for any purpose within 12 weeks prior to the first planned vaccination, greater than or equal to 200 mL within 4 weeks prior to the first planned vaccination, or donation of any amount of blood by apheresis within 2 weeks prior to the planned first vaccination, or planned blood donation or collection of any amount for 90 days after the booster vaccination
• Planned administration of a non-study vaccine anytime between Screening (Visit Screen1) and 30 days following the booster vaccination (Visit B30)
• Current consumption of more than 21 units of alcohol per week for male participants, or 14 units per week for female participants (1 alcohol unit equal to 270 mL full strength beer, 470 mL light beer, 1 glass [100 mL] wine, or 1 measure [30 mL] spirits)
• Unwilling to use appropriate contraception from the first screening visit (Screen1) until 30 days after the final administration of the study drug (excluding females confirmed non-childbearing potential, except via tubal ligation). Adequate contraception is defined as a contraceptive method with failure rate of less than 1% per year when used consistently and correctly and when applicable, in accordance with the product label. Male participants must practice true abstinence* from heterosexual contact or, during sexual contact with a female of childbearing potential, agree to use a condom, in addition to having the female partner use another form of contraception such as an IUD, oral contraceptives, hormonal implants, injectable contraceptive medications, or a tubal ligation. Males with any sexual partners: Males must also agree to use a condom during sexual contact with pregnant women, women of non-childbearing potential or male partners. This criterion must also be followed from the time of first study drug administration until 30 days after the final administration of study drug. Females having undergone tubal ligation as method of sterilisation: must agree to use barrier method of contraception from Screen1 to B360 (or at point of termination).
• True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the participant. [Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception]. For this study, a female is considered to be of non-childbearing potential if they are post-menopausal (defined as greater than 12 months since last menstrual period) or surgically sterilized (i.e., tubal ligation or hysterectomy at least 6 months prior to enrolment).
• Participants who, in the opinion of the Principal Investigator or delegate, should not participate in the study or are not capable of following the study schedule for any reason
• Current smokers who have smoked in the last 3 months and who are unwilling to refrain from smoking for the duration of the study
• Participants who return a positive alcohol or drug screen at Screen1