Selatogrel and Other P2Y12 Inhibitors' Putative Off-Target Effects

Abstract

W e have read with great interest the article entitled "Selatogrel: A Novel Subcutaneous P2Y12 Inhibitor" by Beavers et al, 1 published ahead of print in the Journal of Cardiovascular Pharmacology. We would like to thank the authors for this important summary of the evidence on this new drug but also express concerns that they have not properly interpreted the available data regarding its safety profile. The authors have wrongly deduced the phase 2 data generated in the context of patients with chronic 2 or acute coronary syndrome 3 , whereby no instances of ventricular pauses were actually observed. In particular, the authors stated that among patients with chronic coronary syndrome, common adverse events included dyspnea, dizziness, and ventricular pauses and went on to state that among patients with acute coronary syndrome, 14.9% of them suffered from ventricular pauses with selatogrel (n = 4 with 8 mg and n = 3 with 16 mg), including 2 patients, 1 in each arm, in which they were deemed treatment-emergent serious events. The figures reported by the authors actually refer to ventricular tachycardia, which is a relatively common complication of recent or ongoing myocardial ischemia and was deemed unrelated to the study drug by the investigators. No cases of ventricular pauses were recorded in either of these 2 studies. In addition, the assumption that the mechanism of ventricular pauses would be likely due to potential inhibition of adenosine reuptake is not supported by data from Baumann et al 4 2021, showing that selatogrel is a selective antagonist of the P2Y 12 receptor and does not interfere with adenosine uptake by human red blood cells in vitro at selatogrel concentrations of 10 mM. We disagree with the authors' suggestion that "it had been assumed that dyspnea with ticagrelor and cangrelor was due to the adenosine portions of the molecules" because this was never a widely supported assumption. It was certainly speculated that antagonism of ENT1 by ticagrelor was leading to increased extracellular adenosine levels and thus causing dyspnea, but the observation of similar rates of dyspnea with cangrelor and elinogrel undermined this assumption because these drugs do not antagonize ENT1 and the inactive metabolite of cangrelor is a much weaker ENT1 antagonist than ticagrelor. 5 With such differences in chemical structure between the reversibly binding P2Y 12 receptor antagonists, it seems unlikely that the "pyrimidine core" could have an effect on adenosine receptors that was independent of From the