Bentracimab in Ticagrelor-treated Patients With Uncontrolled Bleeding or Requiring Urgent Surgery or Invasive Procedure

Inclusion Criteria:

Patients will be eligible for inclusion into the study if they meet all of the following criteria:

1. Male or female >18 years of age with documented or verbal informed consent.Emergency consent may be obtained where permitted by local regulations andinstitutional approval.

2. History or documentation of ticagrelor intake within the prior 3 days

3. Patients described below who require urgent reversal of the antiplatelet effects ofticagrelor:

Patients with uncontrolled major or life-threatening bleeding, requiring urgent reversal of the antiplatelet effects of ticagrelor. It is expected that enrolled patients would have characteristics similar to those described below:

• Potentially life-threatening bleeding with signs or symptoms of hemodynamiccompromise, e.g., systolic blood pressure < 90 mm Hg and signs or symptoms of lowcardiac output not otherwise explained

• Bleeding in a critical organ or closed space, such as intracranial, intraspinal,intraocular, retroperitoneal, intra-articular, pericardial, or intramuscular bleedwith compartment syndrome

• Visible, uncontrolled bleeding associated with a corrected hemoglobin level < 8.0g/dL, a fall in hemoglobin level of ≥ 2.0 g/dL (1.24 mmol/L) from a known baseline,or requirement for transfusion of 2 or more units of packed red blood cells (PRBC)

Patients requiring urgent surgery or invasive procedure when it is not medically advisable either to proceed urgently with impaired hemostasis or to delay the urgent procedure for 3 or more days due to the high risk of bleeding. These patients may typically be in any of the following clinical situations:

• Requires urgent surgery or invasive procedure known to be associated with a risk ofsignificant bleeding (such as cardiac surgery, neurosurgery, or major orthopedicsurgery)

• Requires urgent surgery or invasive procedure that may have an adverse proceduraloutcome if hemostasis is impaired (such as neurological, spinal, ophthalmological,urological, or orthopedic surgery)

• At risk of experiencing life-threatening events, such as, shock, myocardialinfarction, or stroke, if significant intraoperative or postoperative bleedingoccurs (such as in elderly patients or patients with underlying cardiac or pulmonarydisease who have limited cardiopulmonary reserve)

Exclusion Criteria:

1. Known sensitivity or contraindication to PB2452 or any of its excipients

2. Patients in whom ticagrelor reversal is not considered urgent, e.g., patients withstable or non-acute conditions who have low hemoglobin due to chronic, low-gradegastrointestinal bleeding or who have stable, remote, or asymptomatic intracranialhemorrhage

3. Patients expected to be clinically unsalvageable, such as, patients with end-stagecancer or patients with overwhelming sepsis

4. Any condition which, in the opinion of the investigator, would make it unsafe orunsuitable for the patients to participate in this study. This includes assessmentof likelihood to cooperate with study follow-up visits and procedures. Knownpregnancy may be exclusionary in some regions or countries as directed by nationalhealth authorities and/or local Institutional Review Boards/Ethics Committees

5. Known use of clopidogrel, prasugrel or ticlopidine within 5 days of study drugadministration; known use of antiplatelet GPIIb/IIIa inhibitors, or cangrelor within 5 half-lives of expected study drug administration; or known use of warfarin,dabigatran, rivaroxaban, apixaban, or edoxaban within 5 half-lives of expected studydrug administration

6. Known recent use (< 5 day) of vitamin K, prothrombin complex concentrate,recombinant factor VIIa, idarucizumab, or andexanet-alfa (coagulation factor Xa (recombinant), inactivated-zhzo)