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US-12617870-B2 - Methods of reversing ticagrelor activity

US12617870B2US 12617870 B2US12617870 B2US 12617870B2US-12617870-B2

Abstract

The present disclosure provides a method of reversing ticagrelor-associated bleeding in a patient by administering an antibody or fragment thereof that binds to ticagrelor.

Inventors

  • John Lee
  • David James Ballance

Assignees

  • SFJ PHARMACEUTICALS X, LTD.

Dates

Publication Date
20260505
Application Date
20190920

Claims (20)

  1. 1 . A method of reversing ticagrelor-associated bleeding, or reducing the risk of said bleeding, in a patient who had previously been administered ticagrelor, comprising administering to the patient a pharmaceutical composition comprising a dose of between about 18 g and about 48 g of an antibody or fragment thereof that binds to ticagrelor ((1S,2S,3R,5S)-3-[7-{[(1R,2S)-2-(3,4-difluorophenyl)cyclopropyl]amino}-5-(propylthio)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)cyclopentane-1,2-diol) or a metabolite or derivative thereof, wherein the antibody or fragment thereof comprises complementarity-determining region (CDR) combinations selected from the group consisting of: a) SEQ ID NO:53 (VH CDR1), SEQ ID NO:54 (VH CDR2), SEQ ID NO:55 (VH CDR3), SEQ ID NO:58 (VL CDR1), SEQ ID NO:59 (VL CDR2), and SEQ ID NO:60 (VL CDR3); b) SEQ ID NO:63 (VH CDR1), SEQ ID NO:64 (VH CDR2), SEQ ID NO:65 (VH CDR3), SEQ ID NO:68 (VL CDR1), SEQ ID NO:69 (VL CDR2), and SEQ ID NO:70 (VL CDR3); and c) SEQ ID NO:73 (VH CDR1), SEQ ID NO:74 (VH CDR2), SEQ ID NO:75 (VH CDR3), SEQ ID NO:78 (VL CDR1), SEQ ID NO:79 (VL CDR2), and SEQ ID NO:80 (VL CDR3).
  2. 2 . The method of claim 1 , wherein the antibody or fragment thereof comprises a combination of heavy chain variable region (VH) and light chain variable region (VL) sequences selected from the group consisting of SEQ ID NO:52 and SEQ ID NO:57; SEQ ID NO: 62 and SEQ ID NO:67; and SEQ ID NO:72 and SEQ ID NO:77.
  3. 3 . The method of claim 1 , wherein the pharmaceutical composition is administered to the patient intravenously.
  4. 4 . The method of claim 3 , wherein the pharmaceutical composition is administered intravenously over about 15 minutes to about 36 hours.
  5. 5 . The method of claim 1 , wherein the pharmaceutical composition is administered in the following schedule: 12 g of the antibody or fragment thereof infused over 10 minutes, followed by 12 g of the antibody or fragment thereof over 6 hours, followed by 12 g of the antibody or fragment thereof over 18 hours.
  6. 6 . The method of claim 1 , wherein the pharmaceutical composition comprises about 50 mg/mL to about 200 mg/mL of the antibody or fragment thereof, about 5 mM to about 50 mM histidine/histidine hydrochloride buffer, about 100 mM to about 300 mM sucrose, and about 0.01% (w/v) to about 1.0% (w/v) polysorbate 80, at about pH 5.5 to about 6.5.
  7. 7 . The method of claim 6 , wherein the pharmaceutical formulation comprises 100 mg/mL of the antibody or fragment thereof, 25 mM histidine/histidine hydrochloride buffer, 290 mM sucrose, and 0.05% (w/v) polysorbate 80, at about pH 6.0.
  8. 8 . The method of claim 1 , wherein the ticagrelor-associated bleeding is major bleeding.
  9. 9 . The method of claim 1 , wherein the patient requires urgent surgery or intervention.
  10. 10 . The method of claim 1 , wherein the patient is at risk of developing, or has been diagnosed with, a disease selected from the group consisting of Acute Coronary Syndrome (ACS), myocardial infarction (MI), unstable angina, stable ischemic heart disease, sickle cell disease, atrial fibrillation, coronary arterial disease, peripheral arterial disease, ischemic stroke requiring one or more coronary stents, carotid artery stents requiring stents following an intracranial aneurysm, and arterio-venous fistulae created for hemodialysis.
  11. 11 . The method of claim 1 , wherein administration of the antibody or fragment thereof restores platelet aggregation to at least 80% of baseline within 1 minute to 60 minutes of starting administration.
  12. 12 . The method of claim 11 , wherein administration of the antibody or fragment thereof restores platelet aggregation within 5 minutes of starting administration.
  13. 13 . The method of claim 11 , wherein the restoration of platelet aggregation is sustained for at least 12 hours after starting administration.
  14. 14 . The method of claim 1 , wherein the antibody or a fragment thereof comprises a CDR combination comprising: SEQ ID NO:73 (VH CDR1), SEQ ID NO:74 (VH CDR2), SEQ ID NO:75 (VH CDR3), SEQ ID NO:78 (VL CDR1), SEQ ID NO:79 (VL CDR2), and SEQ ID NO:80 (VL CDR3).
  15. 15 . The method of claim 1 , wherein the antibody or fragment thereof comprises a combination of heavy chain variable region (VH) and light chain variable region (VL) sequences comprising SEQ ID NO:72 and SEQ ID NO:77.
  16. 16 . The method of claim 1 , wherein the patient has been administered ticagrelor before administration of the anti-ticagrelor antibody or fragment thereof.
  17. 17 . The method of claim 1 , wherein the antibody or fragment thereof is an antibody fragment.
  18. 18 . The method of claim 17 , wherein the antibody fragment is a Fab.
  19. 19 . The method of claim 1 , wherein the pharmaceutical composition is administered in three or more segments, and wherein the first segment is a bolus.
  20. 20 . The method of claim 1 , wherein the patient is at risk of developing, or has been diagnosed with Acute Coronary Syndrome (ACS).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a U.S. National Phase of International Application No.: PCT/US2019/052173, filed Sep. 20, 2019, which claims benefit of Provisional U.S. Application No. 62/733,892, filed Sep. 20, 2018, Provisional U.S. Application No. 62/806,225, filed Feb. 15, 2019, and Provisional U.S. Application No. 62/836,373, filed Apr. 19, 2019, the contents of each of which are incorporated by reference in their entireties for all purposes. DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: a computer readable format copy of the sequence listing (filename: PHAS-037_04US SeqList_ST25.txt, date recorded: Mar. 19, 2021, file size 44 kilobytes). BACKGROUND Acute Coronary Syndrome (ACS) describes a range of conditions associated with sudden reduced blood flow to the heart, including unstable angina and myocardial infarction, or heart attack. ACS is caused by the inappropriate formation of clots in the coronary arteries. These blood clots are made up primarily of platelets, small lens-shaped cells found in the blood that normally aggregate at sites of injury to help stop bleeding. According to the Centers for Disease Control and Prevention, approximately 790,000 Americans have a heart attack every year, and heart attacks are a leading cause of death in the developed world. The primary treatment for ACS is the use of antiplatelet drugs to prevent the worsening of existing clots or to reduce the formation of additional clots. These clots can occur in the heart or in stents that are placed in the blocked coronary artery to keep the blood vessel open or elsewhere in the body. Without antiplatelet drugs, patients are at a significantly increased risk of recurrent heart attacks, stroke and death. The standard of care for ACS patients is dual antiplatelet therapy, or DAPT, which is a combination of aspirin and an inhibitor of a specific receptor found on platelets known as the P2Y12 receptor. This combination, started after a patient experiences a heart attack or other manifestation of ACS, has been shown to significantly reduce platelet aggregation and clot formation and reduce the frequency of recurrent heart attacks, stroke and death. While the antiplatelet drugs used in DAPT therapy have proven effective at improving overall outcomes in ACS patients, their suppression of blood clotting increases patients' risk of major bleeding. Bleeding events in patients on antiplatelet therapy, which can occur spontaneously or as a result of injury or surgery, are classified as minor or major. In the 18,000-patient clinical trial, Platelet Inhibition and Patient Outcomes, or PLATO, conducted by AstraZeneca, ticagrelor was shown to be superior to the antiplatelet drug clopidogrel, marketed under the brand name Plavix, in reducing recurrent heart attack, stroke and death in patients with ACS (Wallentin et al. 2009). However, in both treatment groups, 11% to 12% of patients in the trial suffered major bleeding events, and in 5.8% of patients, these major bleeding events were fatal or life-threatening. The causes of bleeding varied in the trial population. In approximately 3% of the patients on ticagrelor, major bleeding events were spontaneous and not related to any medical procedure, whereas approximately 9% of patients on ticagrelor developed major bleeding that was related to procedures like coronary artery bypass surgery, or CABG (Wallentin et al. 2009). Although the trial protocol recommended that patients who needed CABG stop taking ticagrelor for one to three days prior to surgery, nearly half of all ticagrelor patients needed surgery urgently and could not wait the up to three days for ticagrelor's effect to dissipate so normal blood clotting could be restored. Overall, up to 80% of CABG patients in the trial suffered a major or life-threatening bleeding event related to the surgery, and for those who needed urgent surgery and could not wait three days for ticagrelor to wash out, approximately 50% experienced a fatal or life-threatening bleeding event (Held et al., 2011). While some of this risk was likely associated with patients' underlying conditions, the overall bleeding risk is significantly increased by antiplatelet drugs, and the current US prescribing information for ticagrelor suggests suspension of ticagrelor treatment for five days prior to surgery. Despite the increased bleeding risk, antiplatelet drugs, along with anticoagulant drugs which are used to prevent clots in veins, represent some of the most widely prescribed drugs in the United States due to their lifesaving effects. While both of these classes of drugs increase the risk of bleeding, reversal agents have been developed for anticoagulant drugs, but to date, no reversal agents exist for antiplatelet drugs. In the absence of a reversal agent, physicians have limited treatment options, and sometimes