Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4·5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial

Gusev, Eugene; Martynov, M. Yu.; Nikonov, A A; Shamalov, Nikolay; Semenov, M.P.; Герасимец, Е А; Yarovaya, Elena; Semenov, A M; Archakov, Alexander I.; Markin, S. S.; Aksentiev, S. B.; Yunevich, D S; Алашеев, А. М.; Androfagina, O V; Bobkov, V V; Choroshavina, Ksenia V; Chefranova, J. Y.; Lykov, Yuriy A; Чуприна, С Е; Vorobev, A.A.; Dobrovolskiy, Alexey V; Elemanov, U.A.; Fedaynin, Sergey A; Горбачев, В.И.; Коробейников, Иван Викторович; Greshnova, I. V.; Korsunskaya, L.L.; Никонова, А А; Kudinov, V.A.; Artyushev, Rafael I.; Куценко, В. А.; Nesterova, V. N.; Nizov, Alexey; Girivenko, Alexey I; Orlovsky, Alexey A; Пономарев, Э. А.; Popov, Dmitriy V; Pribylov, Sergey A; Семихин, А. С.; Тимченко, Л. В.; Jadan, O.N.; Zakharov, Sergey A; Chirkov, A; Zhukovskaya, Natalya V.

doi:10.1016/s1474-4422(21)00210-6

Cited by 39 publications

(27 citation statements)

References 29 publications

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“…There are other fibrinolytic agents being evaluated in clinical trials for the treatment of AIS. These include desmoteplase [60][61][62][63][64][65][66], recombinant staphylokinase [67], and modified urokinase [68]; but with their preliminary nonrobust data, their efficacy-safety profiles appeared to be weak.…”

Section: Acute Ischemic Stroke Treatmentmentioning

confidence: 99%

Treatments in Ischemic Stroke: Current and Future

Mosconi¹,

Paciaroni²

2022

Eur Neurol

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Background and Aim: Despite progress made over the last 30 years, stroke is still a leading cause of disability and mortality; likewise, its burden is expected to increase over the next decades, due to population growth and aging. The development of drugs with better safety-efficacy profiles as well as strategies able to improve ischemic stroke management from the pre-hospital setting is needed. Summary: The pathophysiology of ischemic stroke involves multiple pathways resulting in cerebral artery obstruction and brain tissue ischemia. To date, the only approved drug for acute ischemic stroke is intravenous thrombolytic alteplase. Intravenous thrombolysis (IVT) can be administered alone or in combination with endovascular treatment (EVT) with mechanical thrombectomy, in case of large vessel occlusion and generally within 6 h from symptoms onset. The risk of potential bleeding complications, especially symptomatic intracerebral hemorrhage, is one of the reasons for the reluctance to administer IVT. Tenecteplase is a promising alternative fibrinolytic agent, having a better safety profile than alteplase. Moreover, recent evidences have allowed an extension of the IVT ± EVT time window for patients with unknown onset time and for those with a known onset time thanks to the new “tissue-window” approach guided by advanced neuroimaging techniques, which also helps in collateral circulation estimation. Regarding primary-secondary prevention, researchers are focused on improving the efficacy of antithrombotic drugs with a “hemostasis-sparing” approach. Neuroprotective agents are also under development, particularly stem cells. The COVID-19 pandemic has critically stressed global healthcare systems, with collateral damage resulting in access delivery of only emergency care, such as ischemic stroke. Regarding telemedicine, it has had a minor role in acute stroke management, and with the onset of COVID-19, this role will most likely be adopted to increase access and delivery in stroke assessment, but also in the follow-up.

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Section: Acute Ischemic Stroke Treatmentmentioning

confidence: 99%

Treatments in Ischemic Stroke: Current and Future

Mosconi¹,

Paciaroni²

2022

Eur Neurol

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“…В сентябре 2021г в Lancet Neurology были опубликованы результаты исследования ФРИДА -"Неиммуногенная рекомбинантная стафилокиназа в сравнении с альтеплазой у пациентов с ишемическим инсультом (ИИ) не позднее 4,5 ч от начала симптомов" [27], основанием проведения которого послужили приведенные выше результаты высокой эффективности и безопасности препарата Фортелизин® у пациентов с ОИМпST.…”

Section: результатыunclassified

Advanced results of Fortelyzin® use in the FRIDOM1 study and real clinical practice

et al. 2022

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Aim. To study the effectiveness of Fortelyzin® in subgroups with different body weights in patients with ST-segment elevation acute myocardial infarction (STEMI) in the FRIDOM1 study and real clinical practice.Material and methods. Fortelyzin® was administered in a single-bolus dose of 15 mg over 10 seconds, regardless of the body weight of patients. Metalyse® was administered in a single-bolus dose of 30-50 mg over 10 seconds, depending on body weight. The one-year results of the FRIDOM1 study were evaluated by the clinical centers using telephone contact. Monitoring of Fortelyzin® use was carried out by inpatient physicians, emergency doctors and paramedics by filling out a monitoring sheet in the period from June 2013 to December 2021 in 19243 patients with STEMI.Results. In the FRIDOM1 study, the distribution of patients depending on body weight in the Fortelyzin® (n=190) and Metalyse® (n=191) drug groups was as follows: up to 60 kg — 4 people each (p=1,00); from 60 to 70 kg — 21 and 23 (p=0,87); from 70 to 80 kg — 39 and 43 (p=0,71), from 80 to 90 kg — 63 and 47 (p=0,07); from 90 to 100 kg — 30 and 41 (p=0,19); over 100 kg — 33 people (p=1,00) in each group. The effectiveness of thrombolysis according to electrocardiographic (ECG) data in the Fortelyzin® and Metalyse® groups was as follows: up to 60 kg — 75% each (p=1,00); from 60 to 70 kg — 76% vs 83% (p=0,72); from 70 to 80 kg — 82% vs 86% (p=0,76); from 80 to 90 kg — 81% vs 77% (p=0,64); from 90 to 100 kg — 80% vs 81% (p=1,00); over 100 kg — 79% vs 76% (p=1,00); in total — 80% vs 80% (p=0,87). The effectiveness of thrombolysis according to coronary angiography (CAG) (TIMI 2-3) in the Fortelyzin® and Metalyse® groups was as follows: up to 60 kg — 100% vs 50% (p=0,43); from 60 to 70 kg — 81% vs 67% (p=0,48); from 70 to 80 kg — 74% vs 84% (p=0,41); from 80 to 90 kg — 70% vs 72% (p=1,00); from 90 to 100 kg — 67% vs 66% (p=1,00); over 100 kg — 58% vs 64% (p=0,80); in total — 70% vs 71% (p=0,76). The one-year survival rate in the FRIDOM1 study in the Fortelyzin® and Metalyse® groups was 94% (p=0,91). The administration of Fortelyzin® in patients with STEMI caused blood flow restoration according to ECG data in 14624 of 19243 patients (76%), while according to CAG (TIMI 2-3) — in 3422 of 4805 patients (71%). Inhospital mortality was 5% (n=962), while intracranial hemorrhage developed in 0,5% (n=92).Conclusion. The use of Fortelyzin® in the FRIDOM1 study and in real clinical practice in a single-bolus (10 sec) dose of 15 mg in patients with STEMI with any body weight showed its high efficacy and safety, including at the prehospital stage.

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“…Such alarming statistics are a clear motivation to develop efficient thrombolytic treatment strategies. , One of the current clinically approved approaches involves using plasminogen activators, i.e., biocatalytic therapeutic molecules with enzymatic activities that help dissolve fibrin clots by generating plasmin (Plm) on the clot surface. , However, the efficiency of plasminogen activators is still far from ideal and is often accompanied by side effects and bleeding complications. Thus, there is a need to improve current approaches or find new thrombolytic biocatalysts. , Staphylokinase (SAK) is an attractive potential thrombolytic agent due to its fibrin specificity and low production costs. , Even though it is immunogenic, it has the potential to be clinically applied, especially in developing countries where cost effectiveness is prioritized. − Furthermore, a non-immunogenic variant of SAK was recently shown to be non-inferior to the approved drug alteplase in a clinical trial …”

Section: Introductionmentioning

confidence: 99%

Extended Mechanism of the Plasminogen Activator Staphylokinase Revealed by Global Kinetic Analysis: 1000-fold Higher Catalytic Activity than That of Clinically Used Alteplase

et al. 2022

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The plasminogen activator staphylokinase is a fibrin-specific thrombolytic biomolecule and an attractive target for the development of effective myocardial infarction and stroke therapy. To engineer the protein rationally, a detailed understanding of the biochemical mechanism and limiting steps is essential. Conventional fitting to equations derived on the basis of simplifying approximations may be inaccurate for complex mechanisms such as that of staphylokinase. We employed a modern numerical approach of global kinetic data analysis whereby steady-state kinetics and binding affinity data sets were analyzed in parallel. Our approach provided an extended, revised understanding of the staphylokinase mechanism without simplifying approximations and determined the value of turnover number k cat of 117 s −1 that was 10000-fold higher than that reported in the literature. The model further showed that the rate-limiting step of the catalytic cycle is binding of staphylokinase to plasmin molecules, which occurs via an induced-fit mechanism. The overall staphylokinase effectivity is further influenced by the formation of an inactive staphylokinase•plasminogen complex. Here, we describe a quick and simplified guide for obtaining reliable estimates of key parameters whose determination is critical to fully understand the staphylokinase catalytic functionality and define rational strategies for its engineering. Our study provides an interesting example of how a global numerical analysis of kinetic data can be used to better understand the mechanism and limiting factors of complex biochemical processes. The high catalytic activity of staphylokinase (more than 1000-fold higher than that of the clinically used drug alteplase) determined herein makes this thrombolytic agent a very attractive target for further engineering.

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Non-immunogenic recombinant staphylokinase versus alteplase for patients with acute ischaemic stroke 4·5 h after symptom onset in Russia (FRIDA): a randomised, open label, multicentre, parallel-group, non-inferiority trial

Cited by 39 publications

References 29 publications

Treatments in Ischemic Stroke: Current and Future

Treatments in Ischemic Stroke: Current and Future

Advanced results of Fortelyzin® use in the FRIDOM1 study and real clinical practice

Extended Mechanism of the Plasminogen Activator Staphylokinase Revealed by Global Kinetic Analysis: 1000-fold Higher Catalytic Activity than That of Clinically Used Alteplase

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