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Selatogrel, a novel P2Y12 inhibitor for emergency use, achieves rapid, consistent and sustained platelet inhibition following single-dose subcutaneous administration in stable CAD patients

Session New developments in anti thrombotic drug therapy

Speaker Robert Storey

Congress : ESC Congress 2019

  • Topic : cardiovascular pharmacology
  • Sub-topic : Antiplatelet Drugs
  • Session type : Advances in Science
  • FP Number : 2349

Authors : R F Storey (Sheffield,GB), PA Gurbel (Virginia,US), S James (Uppsala,SE), JM Ten Berg (Nieuwegein,NL), J-F Tanguay (Montreal,CA), C Bernaud (Allschwil,CH), J-M Frenoux (Allschwil,CH), A Hmissi (Allschwil,CH), P Van Der Harst (Groningen,NL), AWJ Van't Hof (Maastricht,NL), GD Dangas (New York,US), V Kunadian (Newcastle upon Tyne,GB), DA Gorog (Hertfordshire,GB), D Trenk (Bad Krozingen,DE), DJ Angiolillo (Jacksonville,US)

Authors:
R F Storey1 , PA Gurbel2 , S James3 , JM Ten Berg4 , J-F Tanguay5 , C Bernaud6 , J-M Frenoux6 , A Hmissi7 , P Van Der Harst8 , AWJ Van't Hof9 , GD Dangas10 , V Kunadian11 , DA Gorog12 , D Trenk13 , DJ Angiolillo14 , 1Department of Cardiovascular Science, University of Sheffield - Sheffield - United Kingdom of Great Britain & Northern Ireland , 2Inova Heart and Vascular Institute - Virginia - United States of America , 3Uppsala University, Department of Medical Sciences and Uppsala Clinical Research Center - Uppsala - Sweden , 4St Antonius Hospital, Department of Cardiologie - Nieuwegein - Netherlands (The) , 5Institut de Cardiologie de Montréal, Université de Montréal, Department of Medicine - Montreal - Canada , 6Idorsia Pharmaceuticals Ltd, Therapeutic Area Units - Allschwil - Switzerland , 7Idorsia Pharmaceuticals Ltd, Biometry - Allschwil - Switzerland , 8University Medical Center Groningen - Groningen - Netherlands (The) , 9Maastricht University Medical Centre (MUMC) - Maastricht - Netherlands (The) , 10Mount Sinai Hospital, Division of Cardiology - New York - United States of America , 11Freeman Hospital, Cardiothoracic Centre - Newcastle upon Tyne - United Kingdom of Great Britain & Northern Ireland , 12University of Hertfordshire - Hertfordshire - United Kingdom of Great Britain & Northern Ireland , 13University Heart Center Freiburg-Bad Krozingen, Department of Cardiology and Angiology II - Bad Krozingen - Germany , 14University of Florida College of Medicine - Jacksonville - United States of America ,

Citation:

Background: In the setting of AMI, rapid platelet inhibition is desirable but the onset of pharmacodynamic (PD) effect of oral platelet P2Y12 inhibitors is delayed, sometimes for hours. Subcutaneous (s.c) administration of a rapidly-acting P2Y12 inhibitor would overcome many of the limitations of available therapies. Patients with stable CAD were investigated initially.
Purpose: To characterise the inhibition of platelet aggregation and pharmacokinetics (PK) of a single dose of selatogrel, a novel s.c P2Y12 inhibitor, in patients with stable CAD.
Methods: Patients with stable CAD receiving oral antiplatelet therapy (aspirin and/or oral P2Y12 inhibitor) were randomized to 1 of 8 groups based on treatment (selatogrel or matching placebo), dose (8 mg or 16 mg) and s.c injection site (thigh or abdomen). Venous blood samples were collected into PPACK anticoagulant tubes. Platelet reactivity was assessed by VerifyNow PRU (P2Y12 reaction units) test before and 15 min, 30 min and 1, 2, 4, 8 and 24 h after injection. Light-transmittance aggregometry (LTA; ADP 20 uM) was also performed. PK samples were collected up to 24 h post-dose. Adverse events occurring within 30 days were recorded. Responders were defined as having PRU <100 at 30 min after injection and lasting =3 h.
Results: 345 patients (mean age 65 y; 20% female; 31% diabetes) received selatogrel 8 mg (n=114), selatogrel 16 mg (n=115) or placebo (n=116). 97% were on background therapy with aspirin (or its derivative carbasalate) and 35% with oral P2Y12 inhibitor (clopidogrel 23%, prasugrel 4%, ticagrelor 8%). 89% of subjects were responders to selatogrel 8 mg, 90% to selatogrel 16 mg and 16% to placebo (P<0.0001). At 15 min post-dose, PRU values (mean±SD) were 10±25 with selatogrel 8 mg, 5±10 with selatogrel 16 mg and 163±73 with placebo (Figure). PRU levels were maintained at 2 and 4 h for both doses and gradually returned to pre-dose levels by 24 h post-dose (Figure). LTA results were consistent with the VerifyNow results. PD responses were similar for thigh and abdomen injection sites. Selatogrel was well tolerated: mild dyspnoea (or moderate dyspnoea, n=1, with 16 mg) occurred in 5% and 9% with selatogrel 8 mg and 16 mg, respectively, vs 0% with placebo; dizziness occurred in 4% and 4% vs 1%, respectively, without significant haemodynamic or ECG changes. Bleeding events occurred in 9.6% and 4.3% with selatogrel 8 mg and 16 mg, respectively, vs 6.9% with placebo. Pharmacokinetic data will be presented.
Conclusions: Selatogrel has a rapid PD effect following s.c injection in patients with stable CAD, within 15 min in most patients. The consistent and high levels of P2Y12 inhibition with a single 8 mg or 16 mg dose are sustained for over 4 hours, following which platelet reactivity progressively recovers over 24 h. Selatogrel was well tolerated, with mostly mild, transient dyspnoea observed in <10% patients. These data support further studies of selatogrel for emergency treatment of AMI patients.

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