Pharmacology and potential role of selatogrel, a subcutaneous platelet P2Y₁₂ receptor antagonist

Figures & data

Figure 1. (a) Molecular structure of the novel reversibly binding P2Y₁₂ antagonist selatogrel, shown for comparison alongside the oral P2Y₁₂ antagonist ticagrelor. (b) Illustrative figure demonstrating the temporal effect profile of a single subcutaneous dose of selatogrel on platelet reactivity, compared with an oral loading dose of ticagrelor with (solid line) and without (dotted line) concurrent morphine exposure. ADP, adenosine diphosphate; SC, subcutaneous; PO, per orum.

Table 1. Human studies reported to date of the pharmacodynamics, pharmacokinetics, and safety of selatogrel.

Study	Study phase	n	Population	Study treatment/design	Key pharmacodynamic findings	Key pharmacokinetic findings	Key safety findings
Baldoni et al. 2014 [9]	I	49	Nonsmoking healthy males, 18 to 45 years old, BMI 18 to 32 kg/m^2.	Part I (n = 40): oral dose escalation of ACT-281959 (di-ester pro-drug of selatogrel, doses up to 1000 mg) or placebo, dbRCT. Part II (n = 9): crossover of single oral doses of selatogrel and two formulations of ACT-281959, open-label RCT.	Part I: Although modest effects on PA and PRU were observed, all doses of oral ACT-281959 tested failed to achieve 50% IPA. Part II: An aqueous-organic oral solution of 70 mg ACT-281959 achieved mean >50% IPA, reverting to baseline by 12–24 h. PD of other oral preparations of ACT-281959 or selatogrel not assessed.	Part I: Plasma selatogrel concentration peaked at 4 to 6 h post-dose. None of the doses of ACT-281959 tested achieved mean peak selatogrel levels >IC50. Part II: Of the formulations tested, only the aqueous-organic oral solution of ACT-281959 achieved peak selatogrel levels >IC50, peaking at 2 h post-dose and ~undetectable by 8 h.	No clinically relevant effects on laboratory parameters, ECG, physical examination, vital signs. Headache was most common AE, but occurred at similar rates between active drug and placebo. No bleeding events or dyspnea.
Juif et al 2019 [10]	I	48	Healthy male subjects aged between 19 and 45 years, BMI 18 to 31 kg/m^2.	Randomized to single SC dose of selatogrel 1, 2, 4, 8, 16 or 32 mg, or placebo, dbRCT.	Dose-dependent reduction in PRU, lowest at 30 min, duration of effect dependent on dose, reverted to baseline at all doses tested by around 24 h.	Dose-dependent plasma levels of selatogrel, peaking at 30 min post-injection, undetectable by 8 to 12 h. Plasma concentration of selatogrel correlated with inhibition of PA. Half-life of effect 1.3 to 9.2 h depending on dose.	No clinically relevant effects on laboratory parameters, ECG, physical examination, vital signs. AEs infrequent and not dose-dependent. No bleeding events or dyspnea.
Ufer et al. 2019 [6]	I	6	Healthy males, 45 to 63 years old, mean BMI 25.0 kg/m^2.	Single SC dose of 16 mg [^14C]- radiolabelled selatogrel.	Not assessed	Time to maximum plasma selatogrel ~45 min, plasma half-life 4.7 h. Geometric mean total recovery of [^14C]-radioactivity was 94.9% of which (92.5% in feces, 2.4% in urine). No major metabolites isolated from plasma. M21 (by gluconuridation) was most abundant metabolite in urine and A1 (by mono-oxidation) in feces.	No serious adverse events or clinically relevant change of laboratory, vital sign or ECG data. 2/6 had vasovagal presyncope after injection and 1/6 insomnia. No reported bleeding or dyspnea.
Storey et al. 2019 [11]	II	345	Patients receiving background oral antiplatelet therapy for stable CAD or MI >3 months prior to enrollment.	Single dose of selatogrel SC 8 mg vs 16 mg vs placebo, 1:1 randomization to thigh or abdomen injection site, dbRCT.	8 mg and 16 mg achieved significant inhibition of ADP-induced PA and reduction in PRU achieved by 30 min post-dose, sustained for at least 8 h and returning to near baseline by 24 h.	Dose-dependent peak in plasma selatogrel at 30 min post-dose, falling in a logarithmic fashion to near-zero at 24 h.	Dyspnea in 5% of 8 mg group, 9% of 16 mg group, 0% on placebo. Mild in all but one case (moderate). Injection/venepuncture site bruising, no major bleeding
Sinnaeve et al. 2019 [12]	II	47	Males or post-menopausal females, age 18 to 85 years, diagnosis of acute type 1 MI with symptom onset between 30 min and 6 h before enrollment.	Randomized 1:1 to a single SC dose of selatogrel 8 mg or 16 mg.	Mean PRU below pre-defined response threshold after 15 min, 91% (8 mg) and 95% (16 mg) were responders at 30 min. Effect persisted for at least 60 min.	Plasma selatogrel peaked at 1 h post-dose, had reduced at 8 h.	Most frequent treatment-emergent AE = ventricular tachycardia (8 mg: n = 4, 16 mg: n = 3). 1 case of mild dyspnea (16 mg). 1 case of mild radial access bleeding (8 mg).

¹⁴C, carbon-14; AE, adverse event; BMI, body mass index; dbRCT, double-blinded randomized controlled trial; CAD, coronary artery disease; ECG, electrocardiogram; IC₅₀, inhibitory concentration required for 50% inhibition; IPA, inhibition of platelet aggregation; MI, myocardial infarction; PA, platelet aggregation; PD, pharmacodynamic; PRU, platelet reactivity units (VerifyNow® P2Y₁₂ test); RCT, randomized controlled trial; SC, subcutaneous.

Figure 2. Potential clinical roles for selatogrel, a novel subcutaneous P2Y₁₂ antagonist. ACS, acute coronary syndrome; PPCI, primary percutaneous coronary intervention.

Baldoni D, Bruderer S, Krause A, et al. A new reversible and potent P2Y12 receptor antagonist (ACT-246475): tolerability, pharmacokinetics, and pharmacodynamics in a first-in-man trial. Clin Drug Investig. 2014;34:807–818.

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Juif PE, Boehler M, Dobrow M, et al. Clinical pharmacology of the reversible and potent P2Y12 receptor antagonist ACT-246475 after single subcutaneous administration in healthy male subjects. J Clin Pharmacol. 2019;59:123–130.

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Ufer M, Huynh C, van Lier JJ, et al. Absorption, distribution, metabolism and excretion of the P2Y12 receptor antagonist selatogrel after subcutaneous administration in healthy subjects. Xenobiotica. 2020;50:427–434.

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Storey RF, Gurbel PA, Ten Berg J, et al. Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes. Eur Heart J. 2019:ehz807. doi: 10.1093/eurheartj/ehz807.

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Sinnaeve PR, Fahrni G, Schelfaut D, et al. Inhibition of platelet aggregation after subcutaneous administration of a single-dose of selatogrel, a novel P2Y12 antagonist, in acute myocardial infarction: a randomised open-label phase 2 study. Eur Heart J. 2019;40(suppl 1):ehz746.0078.

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