Study of Intravenous ZMA001 in Healthy Subjects

Study Description:

ZMA001 is a fully human, monoclonal antibody (IgG1) that inhibits migration of activated monocytes and macrophages and reduces pulmonary vascular remodeling and pulmonary artery pressure in pre-clinical rodent models of pulmonary arterial hypertension (PAH). The current first-in-human, single ascending-dose study will determine the safety, tolerability, and pharmacokinetics of intravenous ZMA001 in healthy subjects.

Objectives:

Primary Objective: Safety and tolerability of ZMA001 in healthy subjects

Secondary Objectives: Determine the pharmacokinetics of ZMA001 in healthy subjects following a single, intravenous dose

Endpoints:

Primary Endpoint: The number of all-cause, treatment-emergent adverse events, grade 1 and above (following CTCAE v5.0 criteria) through day 113

Secondary Endpoints: For each ZMA001 dose level (1.5, 0.25, 0.50, and 1.0 mg/kg), the following will be determined [Timeframe: Pre-infusion, end of infusion, 2, 4, 8, 12, 24, and 48h; Days 8, 15, 22, 29, 57, 85 and 113]:

• Time to peak drug concentration (Tmax)
• Peak drug concentration (Cmax)
• Area under the drug concentration-time curve (AUC)
• Elimination half-life

• INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

• Stated willingness to comply with all study procedures and availability for the duration of the study
• Male* or female, aged 18 to 60 years, inclusive
• In good general health as evidenced by medical history
• Females of childbearing potential agree to use an accepted method of contraception (see below) throughout study participation and for 120 days after study drug infusion.
• Males sexually active with a female partner must agree to use a condom with spermicide for 120 days after study drug infusion or be surgically sterile for at least 90 days before screening. Males must also agree to not donate sperm for 120 days after study drug administration.
• Agreement to adhere to Lifestyle Considerations throughout study duration
• Ability of subject to understand and the willingness to sign a written informed consent document.

• Enrollment of healthy male subjects will be limited to no more than 14 out of the total study cohort of 32 in order to ensure an adequate representation of female subjects.

Accepted methods of contraception for females of childbearing potential:

• Use of an implanted or intrauterine hormonal device for at least 30 consecutive days before study drug infusion
• Use of oral, patch or injectable contraceptives or a vaginal hormonal device for at least 30 consecutive days before study drug infusion
• Use of a non-hormonal intrauterine device for at least 30 consecutive days before study drug infusion
• Two barrier methods such as a diaphragm with spermicide or a condom with spermicide

Exclusion criteria

An individual who meets any of the following criteria prior to informed consent will be excluded from participation in this study:

• Pregnancy or lactation. Females of childbearing potential must have a negative serum Beta-human chorionic gonadotropin test no more than 48 hours from study drug infusion.
• A history of human immunodeficiency virus (HIV) infection.
• History of severe drug or excipient allergy or hypersensitivity
• Known allergy to any of the components of the investigational drug or placebo
• Recent infection or febrile illness within the past 14 days
• Treatment with another investigational drug within the past 30 days or 5 half-lives, whichever is longer
• Any vaccination within the past 4 weeks or receipt of a live-attenuated vaccine within the past 6 months
• Use of tobacco products within the past 3 months
• Illicit drug use (e.g. cocaine, opioids, methamphetamine, PCP) within the past 6 months or positive urine drug screen at Screening Visit
• Marijuana (cannabis) use within the past 30 days or positive urine drug screen at Screening Visit
• History of alcohol abuse within the past 2 years
• Current clinically significant medical illness that is uncontrolled despite appropriate medical treatment including (but not limited to) hematologic, oncologic, renal, endocrine, pulmonary, gastrointestinal, cardiovascular, infectious, hepatic, dermatologic, psychiatric, neurologic, autoimmune or allergic disease
• Body mass index less than 17 or greater than 32 kg/m^2
• Clinically significant abnormal results on clinical blood testing completed at the Screening Visit
• Electrocardiographic evidence of clinically relevant heart disease
• Diabetes mellitus requiring medical treatment
• Received another monoclonal antibody in the past 30 days
• Use of herbal supplements, or similar products within the past 2 weeks
• Blood donation equal to or above 500 mL within 2 months prior to dosing.
• Any other finding that, in the judgment of the Investigator, would increase the risk of having an adverse outcome from participating in the study.

Justification to exclude minors: Given that the vast majority of patients with PAH are >18 years of age and the fact that this is a first in human study, the risks of including children/minors (ie. subjects < 18 yrs of age) are not justified given the limited potential benefits of including these subjects.

Justification to exclude adults >60 years old: Subjects > 60 years of age are more likely to have comorbid medical conditions that could place them at increased risk of participation.