Efficacy and Safety of Sevuparin, a Novel Non-Anti-Coagulant Heparinoid, in Patients with Acute Painful Vaso-Occlusive Crisis; A Global, Multicenter Double-Blind, Randomized, Placebo-Controlled Phase 2 Trial (TVOC01)

Abstract

Background and purpose: There are no currently approved treatments for the vaso-occlusive crises (VOC) associated with sickle cell disease (SCD). In addition to causing pain, vaso-occlusion and the resulting hypoxia cause a reduction in overall life expectancy and increase chronic morbidity. Sevuparin is a novel, non-anticoagulant, low-molecular weight heparin analogue, with a preclinical multi-modal activity profile against VOC relevant targets (i.e. P- and L-selectin, thrombospondin, Von Willebrand factor, fibronectin). Due to its low risk for bleeding side effects, sevuparin can be dosed at levels that were previously unattainable with heparinoids. The present study evaluated whether sevuparin could shorten the time with VOC in hospitalized SCD patients compared to placebo. Patients and methods: This phase II, global, multicenter, randomized, double-blind, placebo-controlled and parallel group clinical trial enrolled patients aged 12 to 50 with a diagnosis of SCD (HbSS, HbSC, HbSβ0-thalassemia, HbSβ+-thalassemia). The study recruited patients across 22 sites in 8 countries (Netherlands, Belgium, Turkey, Oman, Bahrain, Lebanon, Saudi Arabia, and Jamaica). Patients with VOC received sevuparin or placebo (1:1) along with standard of care (SoC) therapy with a requirement for parenteral opioid use. The primary endpoint was time to VOC resolution, measured as the time from IMP start until resolution by fulfilment of the two following criteria: a) freedom from parenteral opioid use (8 ± 2 hours), b) readiness for discharge as judged by the patient or physician (whichever occurred first). In addition to assessing safety, main secondary efficacy measures were related to pain and opioid use. The sample size of 120 VOC resolution events was determined based on an assumed between-arm hazard ratio of 0.60. Results: Overall, 147 subjects were randomized (144 dosed) to sevuparin, n=71 (69); or placebo n=76 (75). The median age of subjects entering the study was 22 years with 72% adults and 62,5 % males. Treatment groups were generally balanced with respect to demographic and baseline characteristics. Sevuparin, infused continuously at 18 mg/kg/day, did not confer any benefit over placebo in the primary endpoint of time to VOC resolution (ITT Cox proportional HR 0.89 (95% CI 0.61-1.30; p = 0.554; Figure 1a), which was also reflected by the secondary endpoint analyses (exemplified in Figure 1b). Most AEs were mild to moderate and transient. The number of SAEs was slightly higher in the placebo group (21/17 [22.4%]; one fatal case with hyperhemolytic crisis) than in the sevuparin group (16/15 [22.1%]). The most commonly reported treatment emergent AEs (TEAEs) are displayed in Table 1. No clinically meaningful differences, imbalances or trends were apparent in TEAEs, laboratory parameters, vital signs, physical examination and ECG data across treatment groups. Conclusions: In this study, one of the largest VOC studies run to date, sevuparin failed to show an improvement of the VOC resolution time and associated measures (pain, opioid use, etc) in patients hospitalized with acute VOC. These results were surprising given both the promise from preclinical models and the clinical efficacy seen with selectin inhibition. It is possible that once full-blown, an acute VOC cannot be limited by sevuparin's mode of action (MoA). The understanding of sevuparin's MoA combined with this negative result may contribute to the notions of VOC causative factors and help inform future therapeutics targeting the VOC. The study is also important given its size and the high patient representation from the eastern Mediterranean and Middle Eastern regions, where SCD is of high prevalence. The comparison of this data with the available data from other VOC studies will be important in helping understand both regional and genetic differences in treatment practices and response to therapeutics. In conclusion, the present study showed that sevuparin treatment was not effective in acute VOC. However, sevuparin's promising safety profile and broad MoA including p-selectin inhibition, may warrant further exploration in the prodromal setting, especially given that sevuparin may be dosed by the patient at home in a convenient, subcutaneous format. Acknowledgements: Modus is grateful for the contributions from Ergomed, the Arabian Gulf University, the study sites, as well as to the patients for participating in this study. Disclosures Al-Khabori: Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; AstraZeneca: Honoraria. Abboud:CRSPR Therapeutics: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Research Funding; GBT: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eli Lilly: Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Other: Travel support; Modus: Research Funding; Novo Nordisk: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Inati:Novonordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; 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; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kristensen:Modus Therapeutics: Employment. Donnelly:Modus Therapeutics: Employment. Ohd:Modus Therapeutics: Employment.

P-Selectin Blockade in the Treatment of Painful Vaso-Occlusive Crises in Sickle Cell Disease: A Spotlight on Crizanlizumab

“…It failed to show benefit in treating VOEs, although it was shown to prevent VOEs and to normalize blood flow in animal studies. 30 Both drugs were ineffective at treating VOEs and accelerating recovery, in agreement with the concept that P-selectin inhibition is not an effective strategy after a VOE has set in. Recently, crizanlizumab-a monoclonal antibody that inhibits P-selectin functionwas studied for its prophylactic use and yielded positive results that led to regulatory approval.…”

Sickle Cell Disease: Current Drug Treatments and Functional Foods with Therapeutic Potential

“…This compound has been shown to be a potent anti-adhesive agent, both in in vitro and in vivo studies, which is crucial in the context of VOCs in SCD. It helps prevent or reduce blood vessel obstruction, a common phenomenon in this condition due to the abnormal adherence of sickle cells to each other and vessel walls [ 66 , 67 ]. Lizarralde-Iragorri, Parachalil Gopalan, Merriweather, Brooks, Hill, Lovins, Pierre-Charles, Cullinane, Dulau-Florea, Lee, Villasmil, Jeffries, and Shet [ 36 ] investigated the effectiveness of isoquercetin in reducing inflammation associated with blood clots (thromboinflammation) in SCD.…”

Drug Therapies for the Management of Sickle Cell Disease

“…Sevuparin, a derivative of LMW heparin, which retains the P-selectin-binding domain of heparin but largely lacks anticoagulant properties, binds to P-and L-selectins, thrombospondin, fibronectin, and von Willebrand factor, inhibits the adhesion of sickle RBCs to stimulated cultured endothelial cells in vitro, and prevents vaso-occlusion with normalization of blood flow in a mouse model of vaso-occlusion 102 . A recently completed randomized, double-blind, placebo-controlled trial found that, although safe, sevuparin did not significantly reduce the time to resolution of vaso-occlusive crisis 103 . A phase II feasibility study of therapeutic-dose unfractionated heparin (NCT02098993) was recently terminated for poor enrollment, but a phase III, randomized, placebo-controlled study of tinzaparin in acute chest syndrome is ongoing (NCT02580773).…”