Study to Evaluate the Safety, Tolerability, PK and PD of PB2452 in Healthy Younger, Older and Elderly Subjects

Phase 2

Completed

Conditions: Healthy

Interventions: Drug: Ticagrelor Oral Tablet - Pre-Treatment
Drug: Placebo - Sodium Chloride
Drug: PB2452 Infusion
Drug: Ticagrelor Oral Tablet - Pre-Treatment and Post-Treatment

Registration Number: NCT03928353

Lead Sponsor: SFJ Pharmaceuticals, Inc.

Brief Summary: 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).

Detailed Description: 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).

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 23

Inclusion Criteria

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

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
History of any acute or chronic medical disorder expected to decrease the life expectancy of the subject
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
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
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)
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
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
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)
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
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
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
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)
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
Positive test result for alcohol or drugs of abuse at Screening or Check-in
Participated in strenuous activity or contact sports within 24 hours before the infusion of study drug or while confined in the clinical site
History of severe or ongoing allergy/hypersensitivity to any drug or biologic therapeutic agent
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)
Previously received PB2452 or had been randomized to receive study drug in an earlier cohort for this study

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
2: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Ticagrelor Oral Tablet - Pre-Treatment	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
4: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Ticagrelor Oral Tablet - Pre-Treatment	PB2452 Infusion or Placebo - Sodium Chloride With Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
5: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Ticagrelor Oral Tablet - Pre-Treatment	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
5: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Ticagrelor Oral Tablet - Pre-Treatment and Post-Treatment	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
1: 18 g PB2452 or Placebo (Ticagrelor Pre-Trx)	Ticagrelor Oral Tablet - Pre-Treatment	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
3: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Placebo - Sodium Chloride	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
5: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Placebo - Sodium Chloride	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
1: 18 g PB2452 or Placebo (Ticagrelor Pre-Trx)	Placebo - Sodium Chloride	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
2: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Placebo - Sodium Chloride	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
4: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Placebo - Sodium Chloride	PB2452 Infusion or Placebo - Sodium Chloride With Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
2: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	PB2452 Infusion	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
5: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	PB2452 Infusion	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
1: 18 g PB2452 or Placebo (Ticagrelor Pre-Trx)	PB2452 Infusion	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses
3: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	PB2452 Infusion	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
4: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	PB2452 Infusion	PB2452 Infusion or Placebo - Sodium Chloride With Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses
3: 18 g or greater PB2452 or Placebo (Ticagrelor Pre-Trx)	Ticagrelor Oral Tablet - Pre-Treatment	PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg BID for a total of 5 doses

Primary Outcome Measures

Name	Time	Method
Number Of Participants With Treatment-emergent Adverse Events (TEAEs) And Serious Adverse Events (SAEs)	Day -3 up to Day 28	An adverse event (AE) is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not it is considered drug-related. A TEAE is defined as any AE not present before exposure to study drug or any AE already present that worsens in intensity or frequency after exposure to study drug. An SAE/suspected unexpected serious adverse reaction if, in the view of either the investigator or Sponsor, it results in any of the following outcomes: death, life-threatening AE, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, or congenital anomaly or birth defect. A summary of serious and all other non-serious adverse events, regardless of causality, is located in the Reported Adverse Events module.
Percent Change In Systolic Blood Pressure From Baseline To Day 28	Day 1 (10, 20, 30, 45, and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Systolic blood pressure measurements were measured at specific time points.
Mean Oral Body Temperature at Baseline	Baseline
Percent Change In Oral Body Temperature From Baseline To Day 28	Day 1 (45 and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Body temperature measurements were measured at specific time points.
Mean Respiratory Rate at Baseline	Baseline
Mean Heart Rate at Baseline	Baseline
Incidence Of Clinically Significant 12-Lead Electrocardiogram (ECG) Findings	Up to Day 28	Number of participants per cohort with clinically significant ECG findings.
Number of Participants With Clinical Laboratory Abnormalities	Day -45 up to Day 28	Number of participants with clinically significant abnormal laboratory findings for hematology, coagulation, serum chemistry, and urinalysis.
Number of Participants With Adverse Events During Physical Examination	Baseline through Day 28	Participants with adverse events noted during physical exam between baseline and end of study.
Mean Diastolic Blood Pressure at Baseline	Baseline
Percent Change In Respiratory Rate From Baseline To Day 28	Day 1 (45 and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Respiratory rate measurements were measured at specific time points.
Percent Change In Heart Rate From Baseline To Day 28	Baseline, Day 1 (10, 20, 30, 45, and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Heart rate measurements were measured at specific time points.
Percent Change In Diastolic Blood Pressure From Baseline To Day 28	Day 1 (10, 20, 30, 45, and 60 minutes post-dose), Day 2, Day 3, Day 7, and Day 28	Diastolic blood pressure measurements were measured at specific time points.
Mean Systolic Blood Pressure at Baseline	Baseline
Participants Experiencing Anti-drug Antibodies (ADAs)	Day -3, Day 1, Day 7, and Day 28	Number of participants who developed ADAs to PB2452.