Background: There is a significant unmet need for treatments to reduce vaso-occlusive crises (VOCs) in sickle cell disease (SCD). Until recently, the only pharmacological treatment approved for reduction of VOCs was hydroxyurea (hydroxycarbamide), and is recommended for children ≥9 months old with SCD. L-glutamine is approved for the reduction of acute complications of SCD in children ≥5 years old, although symptoms can start as early as 5 months of age. Inhibition of platelet activation has been proposed as a potential therapeutic option for SCD. The rationale for the use of antiplatelet therapies in SCD management is based on evidence that platelets participate in the vaso-occlusive process and that platelet activation correlates with the frequency of pain episodes (Ataga et al, 2012). Platelets are activated during the non-crisis steady state (Lee et al, 2006). The antiplatelet drug ticlopidine, which has a similar mechanism of action as ticagrelor (prevention of adenosine diphosphate [ADP]-mediated platelet activation), significantly reduced the frequency of VOCs in patients with SCD (Cabannes et al, 1984). In the phase III DOVE study in pediatric patients, the platelet inhibitor prasugrel was shown to result in a numerical reduction in VOC events with fewer painful crises in the prasugrel group (66%) versus placebo (72%); however, the differences versus placebo did not reach statistical significance (Heeney et al, 2016). Of note is that the prasugrel doses used in DOVE only resulted in a mean platelet inhibition of ~20% (Jakubowski et al, 2017). The low platelet inhibition may have contributed to the lack of efficacy in this study (Heeney et al, 2016). Ticagrelor is an oral, direct-acting, selective, reversibly-binding P2Y12 receptor antagonist that prevents ADP-mediated platelet activation and aggregation. Ticagrelor was approved in 2010 to reduce the rate of cardiovascular death, myocardial infarction, and stroke in adult patients with acute coronary syndromes, and is currently approved in >100 countries. A program is currently ongoing to assess the potential therapeutic benefits of ticagrelor in reducing the occurrence of VOCs in children with SCD. A phase III study (HESTIA3; NCT03615924) is underway to evaluate the efficacy of ticagrelor in reducing the rate of VOCs, as well as the safety and tolerability of ticagrelor versus placebo in SCD pediatric patients 2 to <18 years old. The present phase 1 study (HESTIA4; NCT03492931) was conducted to investigate whether ticagrelor exposure in children <24 months old is similar to that in older children. Thus, the primary objective of HESTIA4 was to determine the pharmacokinetic (PK) properties of ticagrelor in children with SCD aged 0 to <24 months after a single oral dose. This study will enable selection of an appropriate dose for further evaluation of the effect of ticagrelor in preventing VOCs in children <24 months.

Methods: Twenty-one children aged 3-21 months with SCD were given a single, oral dose of ticagrelor (0.1 mg/kg for the age group <6 months and 0.2 mg/kg for the age group ≥6 months.). Four PK blood samples were collected i.e. at 1, 2, 4 and 6 hours post dose from each patient. A follow-up visit was conducted between days 4 to 8 post-dosing. For dose selection in HESTIA4, a pediatric physiologically-based PK model was developed based on physiochemical, in vitro and final PK data from children 2 to <18 years in HESTIA1 (NCT02214121). This model was used to predict ticagrelor exposure in children in the age groups 0 to <6, 6 to <12 and 12 to <24 months. The proposed doses in HESTIA4 were selected for the detection of ticagrelor and active metabolite in plasma after a single dose without causing a pronounced degree of platelet inhibition.

Results: There were no bleeding events reported, and there was only one serious adverse event reported (hospitalization due to bronchiolitis 7 days after dosing, considered not related to ticagrelor). The results show that ticagrelor PK, with weight-based dosing, results in comparable exposure in children aged 0 to <6, 6 to <12 and 12 to <24 months, and that exposure was similar to children aged >24 months.

Conclusion: The present PK results with ticagrelor show a good correlation between predicted and observed exposure, supporting the evaluation of ticagrelor in children with SCD <24 months of age using weight-based dosing. Single-dose ticagrelor, at the doses evaluated, was well tolerated in this population.

Disclosures

Inati:Global Blood Therapeutics: Research Funding; AstraZeneca: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Githanga:AstraZeneca: Other: Member of the steering committee in phase III study in Brilinta Pediatric Program. Abboud:AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Research Funding; Modus: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cela:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Not personal, but on behlalf of the Spanish Pediatric Hematology Society) Funding for the Spanish Hemoglobinopathy registry . Niazi:AstraZeneca: Employment, Equity Ownership. Åstrand:AstraZeneca: Employment. Persson:AstraZeneca: Employment. Berggren:AstraZeneca: Employment. Carlson:AstraZeneca: Employment, Equity Ownership.

OffLabel Disclosure:

Ticagrelor is a P2Y12 platelet inhibitor indicated to reduce the rate of cardiovascular death, myocardial infarction (MI) and stroke in patients with acute coronary syndrome (ACS) or a history of MI. The current study in the submitted abstract is a phase 1 study to characterize the pharmacokinetic and safety profiles of ticagrelor in infants and toddlers aged less than 24 months, with sickle cell disease.

Author notes

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Asterisk with author names denotes non-ASH members.