Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes
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Why the study?
To evaluate the pharmacodynamics and pharmacokinetics of selatogrel, a novel subcutaneous P2Y12 receptor antagonist, in patients with chronic coronary syndromes.
Does single-dose subcutaneous selatogrel provide rapid and potent platelet P2Y12 inhibition compared to placebo in patients with chronic coronary syndromes on background oral antiplatelet therapy?
Key Points
- To evaluate the pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous selatogrel in patients with chronic coronary syndromes receiving background oral antiplatelet therapy.
- Double-blind, randomized placebo-controlled trial (N=345; NCT03384966) evaluating single-dose subcutaneous selatogrel (8 mg, n=114; 16 mg, n=115) versus placebo (n=116).
- Assessed platelet aggregation over 24 hours using the VerifyNow assay and over 8 hours using light transmittance aggregometry, defining responders as having P2Y12 reaction units <100 at 30 minutes persisting for ≥3 hours.
- At 30 minutes post-dose, response rates reached 89% with selatogrel 8 mg and 90% with 16 mg, compared to 16% with placebo (P < 0.0001).
- Mean P2Y12 reaction units at 15 minutes were 10 ± 25 (8 mg) and 4 ± 10 (16 mg) versus 163 ± 73 (placebo), maintaining target inhibition through 8 hours and returning near baseline by 24 hours.
- Selatogrel was well tolerated with peak plasma concentrations at ~30 minutes, and transient dyspnea occurred in 7% of treated patients (16/229; 95% CI: 4–11%).
Structured PICO
Does single-dose subcutaneous selatogrel provide rapid and potent platelet P2Y12 inhibition compared to placebo in patients with chronic coronary syndromes on background oral antiplatelet therapy?
P
Population
345 patients with chronic coronary syndromes (CCS) on background oral antiplatelet therapy
I
Intervention
Single-dose subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115)
C
Comparator
Placebo (n = 116)
O
Outcome
Pharmacodynamic responders (defined as patients having P2Y12 reaction units [PRU] <100 at 30 min post-dose and lasting ≥3 h)surrogate
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Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“What we found was that selatogrel rapidly inhibits platelet clotting activity within 15 minutes and its effect was very consistent across different patients and lasted for up to 8 hours. It was safe and well tolerated and its effect had worn off by 24 hours. This represents a potential solution to two problems in acute heart attack management. Firstly, it could provide a very early anticlotting effect during the critical early phase of a heart attack, reducing the damage to the heart muscle. Secondly, it provides strong anticlotting protection when the patient undergoes stenting of their heart artery, preventing blood clots from blocking off the stent.”
“It is well documented that AMI is caused by blood vessel occlusion, driven by the formation of a platelet-rich thrombus which can be prevented by P2Y12 receptor antagonists. This therapeutic class has been used in the treatment of millions of patients globally and as such, the safety and efficacy profiles are well-established. However, until now the method of administration or the delayed onset of effect means that currently available treatments do not have the desired profile to cover the critical time from onset of AMI symptoms to first medical contact. Scientists at Idorsia have discovered selatogrel, which has great potential to fill this gap for early treatment of AMI.”
“Selatogrel will be developed as drug to be self-administered subcutaneously by the patient. No drug or treatment option is currently available in this space so, if granted, selatogrel will have a unique indication.”
Implication
Single-dose subcutaneous selatogrel provides rapid, potent, and reversible platelet P2Y12 inhibition in patients with chronic coronary syndromes.
Abstract
AIMS: To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). METHODS AND RESULTS: In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4-11%). CONCLUSIONS: Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.
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Cite This Study
Storey et al. (2019) studied this question.