Study to Evaluate the Safety, Tolerability, PK, and PD of PB2452 in Healthy Volunteers

NCT03492385 | Completed Phase 1 Results DMC FDA Drug

• 1 other identifier: PB2452-PT-CL-0001
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief Summary

This is a Phase 1, first-in-human, randomized, double-blind, placebo-controlled, single ascending dose, sequential group study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of PB2452 with and without ticagrelor pretreatment when administered to healthy male and female subjects. Up to 6 dose levels will be evaluated. This study will have up to 10 cohorts and up to a total of approximately 76 subjects with either 4 or 8 healthy young subjects in Cohorts 1 through 9 or approximately 16 older subjects in Cohort 10. The starting dose of PB2452 will be 100 mg and the planned doses for subsequent cohorts are 300, 1000, 3000, 9000, and 18000 mg.

Conditions

Healthy

Outcome Measures

Primary Outcomes (18)

• Number of Participants With Adverse Events (AEs)

  An AE is defined as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug-related.

  Day -3 (Cohorts 4 through 10) or Day -1 (Cohorts 1 through 3) until Day 28

• Number of Participants With Clinically Significant Laboratory Abnormalities

  Number of participants with clinically significant abnormal laboratory findings for hematology, coagulation, serum chemistry, urinalysis and drug tests.

  30 Day - Starting day of dosing

• Change in Diastolic Blood Pressure

  Diastolic blood pressure measurements were measured at specific time points.

  Days 1, 2, 3, 4, 7 and 28

• Change in Systolic Blood Pressure

  Systolic blood pressure measurements were measured at specific time points.

  Days 1, 2, 3, 4, 7 and 28

• Change In Oral Body Temperature

  Body temperature measurements were measured at specific time points.

  Days 1, 2, 3, 4, 7 and 28

• Change In Respiratory Rate

  Respiratory rate measurements were measured at specific time points.

  Days 1, 2, 3, 4, 7 and 28

• Change In Heart Rate

  Heart rate measurements were measured at specific time points.

  Days 1, 2, 3, 4, 7 and 28

• Incidence of Clinically Significant 12-Lead Electrocardiogram (ECG) Findings

  Number of participants per cohort with clinically significant ECG findings.

  60 days - Starting up to 28 days prior to dosing

• Incidence of Clinically Significant Cardiac Telemetry Findings

  Number of participants per cohort with clinically significant cardiac telemetry findings.

  3 Days - Starting 1 day prior to dosing up to 2 days after dosing

• Participants Experiencing Anti-drug Antibodies (ADAs)

  Incidence of Immunogenicity.

  Day -3, Day -1, Day 7, and Day 28

• Maximal Percent of Baseline Platelet Aggregation (PA(Max)) in Cohorts 4-6

  Effectiveness Of Single Ascending Doses Of PB2452. IPA \[maximum (max)\] induced by 20 µM adenosine diphosphate (ADP) at each assessment point.

  Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose.

• Final Extent Percent of Baseline Platelet Aggregation in Cohorts 4-6

  Effectiveness Of Single Ascending Doses Of PB2452. IPA \[final extent\] induced by 20 µM adenosine diphosphate (ADP) at each assessment point.

  Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose.

• Maximal Actual Platelet Aggregation (APA(Max)) (Cohorts 4-6)

  Effectiveness Of Single Ascending Doses Of PB2452 - Inhibition of maximal platelet aggregation.

  Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose (Cohorts 8 and 9 Only).

• Time to Maximum Platelet Aggregation (TPA(Max)) (Cohorts 4-6)

  Effectiveness Of Single Ascending Doses Of PB2452 - Time to IPAmax.

  Before dosing and at 0.5, 1, 2, 3, 6, 12, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose.

• Maximal Percent of Baseline Platelet Aggregation (PA(Max)) (Cohorts 7-10)

  Effectiveness Of Single Ascending Doses Of PB2452 - IPA (max) induced by 20 µM ADP at each assessment point.

  Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose.

• Final Extent Percent of Baseline Platelet Aggregation (Cohorts 7-10)

  Effectiveness Of Single Ascending Doses Of PB2452 - IPA (max) induced by 20 µM ADP at each assessment point.

  Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose.

• Maximal Actual Platelet Aggregation (APA(Max)) (Cohorts 7-10)

  Effectiveness Of Single Ascending Doses Of PB2452 - Inhibition of maximal platelet aggregation.

  Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose

• Time to Maximum Platelet Aggregation (TPA(Max))(Cohorts 7-10)

  Effectiveness Of Single Ascending Doses Of PB2452 - Time to IPAmax

  Before dosing and at 5 min, 0.25, 0.5, 1, 2, 3, 6, 8, 10, 12, 16, 20, 24, and 48 hours after PB2452 infusion and 5th ticagrelor dose. And at 1, 2, 6, and 12 hours after the Day 2 post-MEDI2452 (PB2452) 6th ticagrelor dose.

Study Arms (10)

1: 100 mg PB2452 or Placebo (no Ticagrelor)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride

2: 300 mg PB2452 or Placebo (no Ticagrelor)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride

3: 1000 mg PB2452 or Placebo (no Ticagrelor)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride

4: 1000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride With Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride

5: 3000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride; Drug: Ticagrelor Oral Tablet - Pre-Treatment

6: 9000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride; Drug: Ticagrelor Oral Tablet - Pre-Treatment

7: 18000 mg PB2452 or Placebo (Ticagrelor Pre-Trx)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for a total of 5 doses

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride; Drug: Ticagrelor Oral Tablet - Pre-Treatment

8: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Trx)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride; Drug: Ticagrelor Oral Tablet - Pre-Treatment

9: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre and Post-Trx)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses and 180 mg 24 hours post-dose

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

10: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Txt)

EXPERIMENTAL

PB2452 Infusion or Placebo - Sodium Chloride with Ticagrelor Oral Tablet: 180 mg+90 mg BID for 5 doses

Drug: PB2452 Infusion; Drug: Placebo - Sodium Chloride; Drug: Ticagrelor Oral Tablet - Pre-Treatment

Interventions

PB2452 Infusion DRUG

30 minute - 12 hour infusion

10: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Txt); 1: 100 mg PB2452 or Placebo (no Ticagrelor); 2: 300 mg PB2452 or Placebo (no Ticagrelor); 3: 1000 mg PB2452 or Placebo (no Ticagrelor); 4: 1000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 5: 3000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 6: 9000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 7: 18000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 8: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Trx); 9: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre and Post-Trx)

Placebo - Sodium Chloride DRUG

30 minute - 12 hour infusion

10: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Txt); 1: 100 mg PB2452 or Placebo (no Ticagrelor); 2: 300 mg PB2452 or Placebo (no Ticagrelor); 3: 1000 mg PB2452 or Placebo (no Ticagrelor); 4: 1000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 5: 3000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 6: 9000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 7: 18000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 8: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Trx); 9: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre and Post-Trx)

Ticagrelor Oral Tablet - Pre-Treatment DRUG

Ticagrelor 180 mg + 90 mg BID for 5 doses prior to MEDI2452 (PB2452) or Placebo

10: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Txt); 5: 3000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 6: 9000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 7: 18000 mg PB2452 or Placebo (Ticagrelor Pre-Trx); 8: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre-Trx)

Ticagrelor Oral Tablet - Pre-Treatment and Post-Treatment DRUG

Ticagrelor 180 mg + 90 mg BID for 5 doses prior to MEDI2452 (PB2452) or Placebo and Ticagerlor 180 mg 24 hours following MEDI2452 (PB2452) or Placebo

9: Dose TBD mg PB2452 or Placebo (Ticagrelor Pre and Post-Trx)

Eligibility Criteria

• Age: 18 Years - 50 Years
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• The subject is male or female between 18 and 50 years of age, inclusive.
• The subject has a body mass index 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.
• Aspartate transaminase (AST), alanine transaminase (ALT), total serum bilirubin and alkaline phosphatase levels within the normal range as defined by the clinical laboratory
• White blood cell (WBC) count, platelet count and hemoglobin level within the normal range as defined by the clinical laboratory
• Thyroid stimulating hormone (TSH) level within the normal range as defined by the clinical laboratory at screening
• Prothrombin time (PT) and partial thromboplastin time (PTT) level within the normal range as defined by the clinical laboratory
• Female subjects of childbearing potential must not be pregnant, lactating, or planning to become pregnant before 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 (ie, oral, implantable, patch, or injectable contraceptives in combination with a condom, hormone-containing intrauterine device that has been in place for at least 2 months prior to screening in combination with a condom, double-barrier method \[ie, condoms, sponge, diaphragm, or cervical cap with spermicidal gels or cream\], or vasectomy for male subjects or male partners of female subjects) from 30 days before study drug administration through the end of the study. Women are considered not to be of childbearing potential if they have fulfilled one of the following criteria: documentation of irreversible surgical sterilization (ie, hysterectomy, or bilateral oophorectomy \[not tubal ligation\]), or postmenopausal (defined as amenorrhea for 12 consecutive months following cessation of all exogenous hormonal treatments, and documented plasma follicle-stimulating hormone 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 (eg, condom plus diaphragm with spermicide; condom plus spermicide) during the study and for 30 days after the last dose of study drug, and to refrain from donating sperm for at least 7 days prior to the first dose of study drug until at least 90 days following the last dose of study drug.
• The subject agrees to comply with all protocol requirements.
• The subject is able to provide written informed consent.

You may not qualify if:

• History of any clinically significant acute or chronic disease or medical disorder.
• History or presence of gastrointestinal, hepatic (with the exception of Gilbert's syndrome), or renal disease or renal insufficiency (ie, estimated glomerular filtration rate \<60 ml/min/1.73m2), or any other condition known to interfere with absorption, distribution, metabolism, or excretion of drugs.
• Any clinically significant illness, medical/surgical procedure, or trauma within 4 weeks of the first administration of study drug or any planned surgical procedure that will occur during the study (from screening through the Day 28 follow up visit).
• Any clinically significant abnormal findings in physical examination, vital signs, laboratory assessments, and ECG parameters identified during screening or check-in.
• Any history of arterial or venous thrombosis, including any of the following:
• History of transient ischemic attack, cardiovascular accident, stroke (ischemic or hemorrhagic), unstable angina, myocardial infarction, or peripheral arterial disease
• History of deep venous thrombosis, pulmonary embolus, thrombophlebitis, or cavernous malformations
• Any increased risk of bleeding, including the following:
• Recent history (within 30 days preceding the first dose of study drug) of gastrointestinal bleeding
• Any history of severe head trauma, intracranial hemorrhage, intracranial neoplasm, arteriovenous malformation, aneurysm, or proliferative retinopathy
• Any history of intracranial, intraocular, retroperitoneal, or spinal bleeding
• Any recent (within 30 days preceding the first dose of study drug) major trauma
• History of hemorrhagic disorders that may increase the risk of bleeding (eg, hemophilia, von Willebrand's disease)
• Receiving chronic treatment with nonsteroidal anti-inflammatory drugs (including aspirin \[greater than 100 mg daily\]), anticoagulants, or other antiplatelet agents that cannot be discontinued (including clopidogrel, prasugrel, ticlopidine, dipyridamole, or cilostazol).
• Have taken, within 30 days of screening, any oral or parenteral anticoagulant, including low molecular-weight heparin

Sponsors & Collaborators

• SFJ Pharmaceuticals, Inc.: lead

Study Sites (1)

PPD

Austin, Texas, 78744, United States

Location

Related Publications (1)

• Bhatt DL, Pollack CV, Weitz JI, Jennings LK, Xu S, Arnold SE, Umstead BR, Mays MC, Lee JS. Antibody-Based Ticagrelor Reversal Agent in Healthy Volunteers. N Engl J Med. 2019 May 9;380(19):1825-1833. doi: 10.1056/NEJMoa1901778. Epub 2019 Mar 17.

  PMID: 30883047 DERIVED

MeSH Terms

Interventions

Aftercare

Intervention Hierarchy (Ancestors)

Continuity of Patient Care; Patient Care; Therapeutics; Health Services; Health Care Facilities Workforce and Services; Primary Health Care; Comprehensive Health Care; Patient Care Management; Health Services Administration

Results Point of Contact

• Title: Michele LaRussa SVP, Chief Regulatory Officer
• Organization: SFJ Pharmaceuticals, Inc.

Bentracimab.General@SFJ-Pharma.com

925-223-6233

Study Officials

• LuAnn Bundrant, MD

  PPD Development, LP

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 2, 2018
• First Posted: April 10, 2018
• Study Start: April 3, 2018
• Primary Completion: September 18, 2018
• Study Completion: September 18, 2018
• Last Updated: November 4, 2024
• Results First Posted: November 4, 2024

Record last verified: 2024-08

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)