Findings set stage for self-injection strategy

An injection of a novel potent, highly selective, reversible P2Y12 inhibitor achieved an antiplatelet response within 15 minutes in patients with acute myocardial infarction (AMI), researchers reported in the Journal of the American College of Cardiology.

Moreover, that response to the drug — selatogrel (ACT-246475) — was achieved with no increased safety signal, wrote Peter Sinnaeve, MD, PhD of the Department of Cardiovascular Medicine, University Hospitals, Leuven, Belgium, and colleagues.

Achieving rapid, and safe, platelet inhibition is a critical factor in AMI, and for decades clopidogrel, an oral thienopyridine, was the go-to choice, but it and prasugrel — a newer thienopyridine — are irreversible. The nonthienopyridine, ticagrelor, is reversible.

Both prasugrel and ticagrelor have the benefit of being faster acting than clopidogrel, but for patients with AMI, the antiplatelet action of even the “faster” oral agents is delayed, which makes an agent that can be effective with a single injection highly valuable. If safety and efficacy for such an agent could be confirmed, it would pave the way for patients to self-inject the drug to stop recurrent AMI.

Studies in healthy subjects found that “a single dose of subcutaneous selatogrel induced rapid, profound, and dose-dependent inhibition of platelet aggregation,” Sinnaeve and colleagues wrote.

In this dosing study, they assigned 24 AMI patients to an 8 mg dose of selatogrel and 23 to a 16 mg dose, plus oral antiplatelet therapy (ticagrelor n=43; clopidogrel n=1). The average age of patients was 69 and 72% were men.

“The proportion of responders 30 min post-dose was 91% (one-sided 97.5% confidence interval [CI]: 80%-100%) and 96% (97.5% CI: 87%-100%) with 8 and 16 mg, respectively (P values for responders >85% target; P = 0.142 and P = 0.009, respectively),” they wrote. “A similar response rate was observed at 15 min (8 mg: 75% [97.5% CI: 58%-100%]; 16 mg: 91% [97.5% CI: 80%-100%]), which was sustained at 60 min post-dose (8 mg: 75% [97.5% CI: 58%-100%]; 16 mg: 96% [97.5% CI: 87%-100%]). At 15 min, median P2Y12 reaction units was 51 (range: 4 to 208) for 8 mg and 9 (range: 2-175) for 16 mg.”

There were no injection site (thigh) reactions, and overall adverse events were mild. The most common treatment emergent adverse event was “ventricular tachycardia (8 mg, n = 4; 16 mg, = 3). Ventricular tachycardia was reported as a treatment emergent serious adverse event in 2 patients (8 mg, n = 1; 16 mg, n = 1). Dyspnea of mild intensity occurred in 1 patient (16-mg group), which started 35 min after selatogrel injection, lasted approximately 23 h, and was considered related to selatogrel by the investigator.”

And, the authors noted that there were no major bleeding events in either dose group, which was notable given the pronounced antiplatelet response.

There were, however, a number of limitations to the study, and the authors cautioned that, “although the study was adequately powered to assess the proportion of responders at 30 min (primary endpoint), the analyses and associated P values need to be cautiously interpreted due to the small study population size.” Moreover, this was an open-label study with no placebo arm — a clear limitation.

“Finally, only the VerifyNow P2Y12 test was used to assess the platelet response to selatogrel in our study, with cutoff values for endpoints based on arbitrary thresholds. VerifyNow was chosen above others (light-transmission aggregometry and vasodilator stimulated phosphoprotein) because of its well-studied standardization and low volume of blood required (which is important for a high-risk population of patients with AMI) but also to be consistent with previous clinical studies including a parallel study in patients with chronic coronary syndrome,” they added.

In an editorial that accompanied the study, Johanne Silvain, MD, PhD, and colleagues from the ACTION Study Group, Institut de Cardiologie, Pitié-Salpêtrière Hospital, in Paris, noted that the design of the study “makes it difficult to apprehend the pharmacodynamic effect attributed to selatogrel itself as patients were also treated by a loading dose of ticagrelor. However, a strong P2Y12-mediated platelet inhibition could be noted as fast as 15 min after the injection of the 16-mg dose of selatogrel, with data on pharmacokinetic showing that selatogrel plasma concentration peaked at 30 min for the 16-mg dose and at 60 min for the 8-mg dose.”

Silvain and colleagues pointed out that a phase III study of the 16 mg dose of selatogrel in patients with recurrent AMI is in the planning stages.

“This future clinical trial is exciting as it carries a lot of promise, but it also raises several clinical challenges. How does one educate the right patient to be able to administer the drug at the right time to avoid differential diagnosis? What is the risk of bleeding associated with self-administration of selatogrel in patients already treated by an antiplatelet drug without confirmed diagnosis of acute MI? Will the pharmacological specificity of selatogrel — fast action and short effect in time — be sufficient to provide a net clinical benefit in all coronary patients suspected with a recurrent acute MI? Whereas the rationale is strong for the utility of such a strategy in patients with STsegment elevation MI, the results of a meta-analysis and a recent post hoc analysis of the ACCOAST (A Comparison of Prasugrel at PCI or Time of Diagnosis of Non-ST Elevation Myocardial Infarction) trial question the benefit of pre-treatment by a P2Y12 inhibitor itself in the setting of non–ST-segment elevation MI. For now, we just know that this novel class of P2Y12 inhibitor has the potential to save time in terms of early platelet inhibition,” Silvain et al wrote.

  1. In a small study, a single subcutaneous injection of selatogrel rapidly inhibits ADP-induced platelet aggregation for at least 60 minutes in patients with AMI.

  2. Be aware that randomized trials are needed to confirm the safety and efficacy of self-administered, subcutaneous selatogrel in patients with suspected recurrent AMI.

Peggy Peck, Editor-in-Chief, BreakingMED™

Sinnaeve has received consultancy and/or speaker fees and grants from AstraZeneca and Daiichi-Sankyo, all of which were collected institutionally; and is a clinical investigator for the Fonds voor Wetenschappelijk Onderzoek—Vlaanderen.

Silvain has received consulting fees, lecture fees, or travel support from AstraZeneca, Bayer Health Care SAS, Boehringer Ingelheim France, CSL Behring SA, Gilead Science, Sanofi France, Terumo France SAS, Abbott Medical France SAS, Biotronik, and Zoll; and is a stockholder of Pharmaseeds.

Zeitouni has received research grants from Institut Servier and Fédération Francaise de Cardiologie; and has received lecture fees from Bristol-Myers Squibb and Pfizer.

Kerneis has received research grants from Institut Servier, Federation Francaise de Cardiologie, and Sanofi; and has received consulting fees from Bayer, Sanofi, and Servier.

Cat ID: 358

Topic ID: 74,358,730,358,192,925