This is a Phase 2A, randomized, double-blind, placebo-controlled, single dose, sequential group study to evaluate the safety, tolerability, PK, and PD of PB2452 vs matching placebo with ticagrelor (with or without acetylsalicylic acid (ASA)) pretreatment when various dose levels and administration regimens are administered to healthy younger (ages 18 to 50), older (ages 50 to 64 years) and elderly (ages 65 to 80 years) male and female subjects.

Up to 5 dose levels and/or administration regimens will be evaluated in up to 5 cohorts. Each cohort will include approximately 8 to 12 subjects randomized in a 3:1 ratio (PB2452:placebo).

The study will consist of a Screening period, a Check-in day and Pretreatment Period, an on-site Randomization/Treatment day, 3 days on-site for treatment and safety monitoring, a Follow-up Visit (Day 7), and a Final Follow-up visit (Day 28). Seven days prior to Randomization, subjects in Cohorts 1 and 2 will be administered acetylsalicylic acid (ASA) 81 mg orally once daily (QD) until the final dose on the morning of Day 1 before receiving study drug. A ticagrelor 180 mg oral dose will be administered on the morning of Day -2 followed by either 90 mg or 180 mg every 12 hours (BID) until the 5th dose has been administered on the morning of Day 1.

On Day 1, subjects who meet all the inclusion criteria and none of the exclusion criteria will be randomized in a ratio 3:1 (PB2452:placebo), to receive an IV dose of PB2452 or placebo 2 hours following the 5th ticagrelor dose. Subjects may be discharged from the clinical site between Days 3 and 7 inclusive and will return for a Follow-up visit on Day 7, if already discharged, and on Day 28 (±2 days).

Inclusion Criteria:

1. The subject provides written informed consent and agrees to comply with all protocol requirements.

2. The subject is male or female between 18 and 80 years of age, inclusive (50 to 80 years for Cohorts 1-2, 18 to 50 years for Cohorts 3-5).

3. The subject has a body mass index (BMI) between 18 and 35 kg/m2 and a weight of ≥50 kg but ≤120 kg, inclusive, at Screening.

4. The subject is considered by the investigator to be in good general health, as determined by medical history, clinical laboratory test results, vital sign measurements, 12 lead ECG results, and physical examination findings at Screening. Older and elderly subjects with chronic, stable, and well-controlled medical conditions are eligible provided they meet all other inclusion/exclusion criteria. Some examples of stable and well-controlled medical conditions include but are not limited to:

   • Hypertension (HTN) controlled with ≤2 antihypertensive drugs
   • Diabetes controlled with diet/exercise or treated with up to 2 oral diabetes medications
   • Subjects with diabetes must have a glycated hemoglobin HbA1c ≤8 mg/dL at Screening.
   • Mild hepatic enzyme elevation (aspartate aminotransferase (AST) or alanine transaminase (ALT) <1.5 x ULN or total bilirubin <1.2 x ULN)
   • Controlled hyperlipidemia (defined with a Screening low density lipoprotein LDL <160 mg/dL)

5. Specific inclusionary laboratory values at Screening and Check-in require:

   • White blood cell (WBC) count, platelet count, hemoglobin (Hgb) level within normal range, as defined by the clinical laboratory
   • Thyroid stimulating hormone (TSH) level within normal range, as defined by the clinical laboratory at Screening
   • Prothrombin time (PT) and partial thromboplastin time (PTT) level within normal range, as defined by the clinical laboratory

6. Subjects taking medications for well-controlled medical conditions must have been on a stable dose (meaning no changes in dose) for at least 30 days prior to Screening visit.

7. Older and elderly subjects entering the study who are not already taking daily ASA must be willing to start an 81 mg daily dose of ASA on Day -7 and continue daily dosing until the final dose is administered on the morning of Day 1. Subjects entering the study who are already taking ASA daily will be administered 81 mg ASA daily between Day -7 and Day 1 and must suspend further ASA dosing until discharge from the clinical facility.

8. Female subjects of childbearing potential must not be pregnant, lactating, or planning to become pregnant for 3 months after the last dose of study drug, and have a negative serum pregnancy test at Screening and Check-in. Female subjects of childbearing potential must use 2 effective methods of birth control from 30 days before study drug administration through to the end of the study.

   • Effective birth control methods include oral, implantable, patch, or injectable contraceptive hormone treatment, hormone-containing intrauterine device that has been in place ≥2 months prior to Screening, sponge, diaphragm, or cervical cap with spermicidal gel or cream for female subjects or condom or vasectomy for male subjects.
   • Women are considered to not be of childbearing potential if they have fulfilled one of these criteria: documentation of irreversible surgical sterilization (i.e., hysterectomy or bilateral oophorectomy [not tubal ligation]) or are postmenopausal (defined as amenorrhea for 12 consecutive months following cessation of all exogenous hormonal treatments, and documented plasma follicle-stimulating hormone (FSH) level >40 IU/mL) or amenorrhea for 24 consecutive months.
   • Male subjects with partners of childbearing potential must agree to use appropriate and effective measures of contraception (e.g., condom plus diaphragm with spermicide, condom plus spermicide) during the study and for 30 days after the last dose of study drug, and refrain from donating sperm for ≥90 days following the last dose of study drug.

Exclusion Criteria:

1. Concern the subject may be unable to comply with study procedures and/or follow up, or, in the opinion of the investigator, the subject is not suitable for entry into the study

2. History of any acute or chronic medical disorder expected to decrease the life expectancy of the subject

3. History or presence of gastrointestinal (GI), hepatic (with the exception of Gilbert's syndrome), or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs

4. Significant renal insufficiency, as indicated by estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m2 according to the Modification of Diet in Renal Disease (MDRD) equation

5. Any clinically significant (CS) acute illness, medical/surgical procedure, or trauma within 4 weeks of administration of study drug or any planned surgical procedure that will occur during the study (from Screening through the Day 28 [±2 days] Follow-up visit)

6. Any CS abnormal findings in physical examination, vital signs, laboratory assessments, and ECG parameters identified during Screening or Check-in. Note: abnormal results may be repeated for confirmation immediately after the first out of range measurement. Abnormal vital signs may be repeated twice if needed, immediately after the first abnormal result and/or after the subject has rested for at least 10 minutes.

   Specific vital sign exclusionary criteria occurring after 10 minutes of supine rest are any of the following:

   • Systolic blood pressure (SBP) <100 or >160 mm Hg
   • Diastolic blood pressure (DBP) <40 or >95 mm Hg
   • Resting heart rate (HR) <50 or >100 beats per minute (bpm)

   Specific exclusionary criteria for ECG parameters at Screening or Check-in include any of the following:

   • Prolonged Fridericia-corrected QT interval (QTcF) >450 milliseconds (msec)
   • Shortened QTcF <340 msec, or pause >3 seconds
   • Family history of long QT syndrome

7. Any specific contraindication to Brilinta® as described in the Brilinta® prescribing information and:

   • History of intracranial hemorrhage, active bleeding, or hypersensitivity or allergic reaction to ticagrelor or any component of the product
   • Any history of severe head trauma, intracranial neoplasm, arteriovenous malformation, aneurysm, or proliferative retinopathy
   • Any history of intraocular, retroperitoneal, or spinal bleeding
   • Have taken, within 30 days of Screening, any oral or parenteral anticoagulant, including low molecular-weight heparin
   • Stool sample testing positive for occult blood within 3 months of Screening or at any time during the Screening Period

8. Receiving chronic treatment with nonsteroidal anti-inflammatory drugs (NSAIDS; [including ASA >100 mg daily]), anticoagulants, or other antiplatelet agents that cannot be discontinued 14 days prior to randomization (including clopidogrel, prasugrel, ticlopidine, dipyridamole, or cilostazol)

9. Positive test result for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, or human immunodeficiency virus (HIV) types 1 or 2 antibodies at Screening

10. Concomitant oral or IV therapy with strong cytochrome P450 3A4 (CYP3A) inhibitors, CYP3A substrates with narrow therapeutic indices, or strong CYP3A inducers, which cannot be stopped within at least 5 half-lives, but not fewer than 10 days, before randomization

11. Consumption of grapefruit or grapefruit juice, Seville orange or Seville orange containing products (e.g., marmalade), or xanthine containing products within 48 hours before dosing with study drug

12. Prescription or over the counter (OTC) medications within 14 days before the first dose of study drug unless specifically allowed by protocol. (Permitted medications include multivitamins, paracetamol [up to 2g per day], and/or treatments for chronic stable diseases, provided the drug and dose have been stable for ≥30 days prior to administration of study drug)

13. Has received another investigational drug (defined as a small molecule or biologic compound which has not been approved for marketing) within 30 days of the administration of study drug in this study or within 5 half-lives of the prior study drug, whichever is longer

14. Positive test result for alcohol or drugs of abuse at Screening or Check-in

15. Participated in strenuous activity or contact sports within 24 hours before the infusion of study drug or while confined in the clinical site

16. History of severe or ongoing allergy/hypersensitivity to any drug or biologic therapeutic agent

17. Involvement with any previous Sponsor's or study site employee or their close relatives (e.g., spouse, parents, siblings, or children whether biological or legally adopted)

18. Previously received PB2452 or had been randomized to receive study drug in an earlier cohort for this study