Sevuparin for the treatment of acute pain crisis in patients with sickle cell disease: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Biemond, Bart J.; Tombak, Anıl; Kılınç, Yurdanur; Al-Khabori, Murtadha; Abboud, Miguel R.; Nafea, Mohammed; Inati, Adlette; Wali, Yasser; Kristensen, Jørgen Kvist; Kowalski, Jan; Donnelly, Ellen; Öhd, John

doi:10.1016/s2352-3026(21)00053-3

Cited by 29 publications

(15 citation statements)

References 23 publications

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“…Since the discovery of SCD in modern history in 1910, there are only four FDA approved drugs for the prevention of pain in SCD, three of which received approval only in the last 5 years [ [10] , [11] , [12] ]. Currently, there is no FDA approved drug for the treatment of acute VOC, although a few drugs have been tested in clinical trials and without successful results [ [13] , [14] , [15] ]. The conduct of clinical trials in SCD has been challenging in this minority population for an otherwise complicated clinical outcome of pain.…”

Section: Discussionmentioning

confidence: 99%

Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department

Majumdar¹,

McKinley²,

Chamberlain³

et al. 2023

Contemporary Clinical Trials Communications

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Section: Discussionmentioning

confidence: 99%

Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department

Majumdar¹,

McKinley²,

Chamberlain³

et al. 2023

Contemporary Clinical Trials Communications

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“…At present, we conclude that ticagrelor is not effective for the prevention of vaso-occlusive crises in pediatric patients with the SCD genetic traits HbSS and HbS/β 0 . Unfortunately, the negative result of the HESTIA3 trial of ticagrelor joins a list of negative results for other investigational agents in SCD, including senicapoc, 38 prasugrel, 23 regadenoson, 39 sevuparin, 40 poloxamer 188, 41 olinciguat, 42 and rivipansel. 43 There continues to be a significant unmet need for prevention and treatment of vaso-occlusive crises in SCD.…”

Section: Discussionmentioning

confidence: 99%

Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study

Heeney

Abboud

Githanga

et al. 2022

Blood

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The phase 3 HESTIA3 study assessed the efficacy and safety of the reversible P2Y12 inhibitor ticagrelor versus placebo in preventing vaso-occlusive crises in pediatric patients with sickle cell disease (SCD). Patients aged 2 to 17 years were randomly assigned 1:1 to weight-based doses of ticagrelor or matching placebo. The primary endpoint was the rate of vaso-occlusive crises, a composite of painful crises and/or acute chest syndrome (ACS). Key secondary endpoints included number and duration of painful crises, number of ACS events, and number of vaso-occlusive crises requiring hospitalization or emergency department visits. Exploratory endpoints included the effect of ticagrelor on platelet activation. In total, 193 patients (ticagrelor: N = 101; placebo: N = 92) underwent randomization at 53 sites across 16 countries. The study was terminated 4 months before planned completion for lack of efficacy. Median ticagrelor exposure duration was 296.5 days. The primary endpoint was not met: estimated yearly incidence of vaso-occlusive crises was 2.74 in the ticagrelor group and 2.60 in the placebo group (rate ratio: 1.06; 95% confidence interval: 0.75-1.50; P =.7597). There was no evidence of efficacy for ticagrelor versus placebo across secondary endpoints. Median platelet inhibition with ticagrelor at 6 months was 34.9% at pre-dose and 55.7% at 2 hours post-dose. Nine patients (9%) in the ticagrelor group and eight patients (9%) in the placebo group had at least one bleeding event. In conclusion, no reduction of vaso-occlusive crises was seen with ticagrelor versus placebo in these pediatric patients with SCD. Trial registration: ClinicalTrials.gov NCT03615924.

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“…Heparin derivatives and mimetics with reduced anticoagulant activities may be safe at much higher concentrations than heparin itself, as indicated in trials of heparin derivatives for conditions other than sepsis. For the modified heparin roneparstat, 300–400 mg/kg has been recommended on the basis of a Phase 1 trial [ 198 ]; 18 mg/kg/day was the dose used in a trial of the modified LMWH sevuparin [ 199 ] and 100 mg/kg of pixatimod was tolerated well [ 200 ]. The introduction of heparin mimetic compounds as anti-inflammatory agents in sepsis treatment might therefore complicate the use of anticoagulant heparin to treat coagulopathy.…”

Section: Clinical Trials Of Heparin In Sepsismentioning

confidence: 99%

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

Hogwood

Gray

2023

Pharmaceuticals

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Sepsis is a life-threatening hyperreaction to infection in which excessive inflammatory and immune responses cause damage to host tissues and organs. The glycosaminoglycan heparan sulphate (HS) is a major component of the cell surface glycocalyx. Cell surface HS modulates several of the mechanisms involved in sepsis such as pathogen interactions with the host cell and neutrophil recruitment and is a target for the pro-inflammatory enzyme heparanase. Heparin, a close structural relative of HS, is used in medicine as a powerful anticoagulant and antithrombotic. Many studies have shown that heparin can influence the course of sepsis-related processes as a result of its structural similarity to HS, including its strong negative charge. The anticoagulant activity of heparin, however, limits its potential in treatment of inflammatory conditions by introducing the risk of bleeding and other adverse side-effects. As the anticoagulant potency of heparin is largely determined by a single well-defined structural feature, it has been possible to develop heparin derivatives and mimetic compounds with reduced anticoagulant activity. Such heparin mimetics may have potential for use as therapeutic agents in the context of sepsis.

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Sevuparin for the treatment of acute pain crisis in patients with sickle cell disease: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

Cited by 29 publications

References 23 publications

Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department

Design of an adaptive randomized clinical trial of intravenous citrulline for sickle cell pain crisis in the emergency department

Ticagrelor vs placebo for the reduction of vaso-occlusive crises in pediatric sickle cell disease: the HESTIA3 study

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

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