S853 Successor: A Multicenter Retrospective Noninterventional Follow‐up Study in Patients With Sickle Cell Pain Crises Who Previously Participated in the Sustain Trial in the United States

Abstract

Background: Haemophilia A is caused by deficiency of Factor VIII (F.VIII), an essential blood-clotting cofactor. Prophylaxis or on-demand treatment with recombinant FVIII forms the current standard of care to prevent bleeding in Haemophilia A patients in the developed world. However, approximately 30% of severe haemophilia A patients develop inhibitory antibodies against F.VIII. Moreover, FVIII treatment requires venous access which is burdensome. The recent successful clinical trials and subsequent regulatory approval of a F.VIII-mimetic bispecific antibody, Hemlibra, in Haemophilia A patients with inhibitors have provided much needed hope for suffers and their family. However, whilst Hemilibra represents a major breakthrough in the field, there remain some concerns about balancing the risks of bleeding with those of thrombosis when using this agent. Aims: To develop a new fully human FVIII mimetic bispecific antibody that can support the assembly of a functional Factor IXa (F.IXa) and Factor X (F.X) complex, thereby replacing F.VIII function in vivo. Methods: Using Kymab's bispecific antibody platform, we developed KY1049, a fully human common light chain (CLC) bispecific antibody, to test as an effective functional mimetic of F.VIII. KY1049 bispecific heterodimer was purified using standard Protein A chromatography, followed by cation ion exchange chromatography (cIEX). The mass and heterodimer purity of the bispecific molecule was confirmed using Mass Spectrometry (MS). A combination of in vitro and ex vivo assays was used to characterize the cIEX purified bispecific antibody, including chromogenic FXase and Activated Partial Thromboplastin Time (aPTT). The affinities of the FIX arm and FX arm of KY1049 bispecific to FIX and FX, respectively, were determined using Surface Plasmon Resonance (SPR). Results: cIEX purified KY1049 molecule was confirmed as a single species by MS. After denaturing, the molecular weights of the two heavy chains and one light chain matches in silico predicted molecular weights. Purified KY1049 actively generated activated F.X (F.Xa) and functionally rescued the clotting defect in F.VIII-depleted plasma in the aPTT assay. Importantly, ex vivo activities of KY1049 indicates its therapeutic benefit is likely to be similar in efficacy to Hemlibra. KY1049 binds F.IX and F.X simultaneously by SPR, but the affinities are different from those reported of Hemlibra. Summary/Conclusion: We have developed KY1049, a FVIII mimetic bispecific antibody, that demonstrates biological activities comparable to those reported for Hemlibra. Its therapeutic benefit is likely to be at least as effective as Hemlibra. Furthermore, initial analysis of the KY1049 molecule also showed some differences between the two molecules which could be harnessed to enhance its physical properties and activity.

Systematic Review of Crizanlizumab: A New Parenteral Option to Reduce Vaso‐occlusive Pain Crises in Patients with Sickle Cell Disease

“…Another trial (the SUCCESSOR trial) retrospectively assessed the subsequent occurrence of VOCs in patients who completed the SUSTAIN study. This study reported that patients previously treated with crizanlizumab (5 mg/kg) maintained a similar time to first VOC compared with the same measurement while on treatment in SUSTAIN, suggesting a prolonged effect of crizanlizumab 24 . The abstract was presented at the 24th European Hematology Association Congress in 2019.…”

Current and Future Therapeutics for Treating Patients with Sickle Cell Disease

“…A multicenter, retrospective, non-interventional study (SUCCESSOR) followed up on the SUSTAIN study participants. Follow-up data report similar results, where VOCs increased after the trial compared to when receiving the intervention [51]. However, beyond this, few studies evaluating its real-world effectiveness have been completed, and many ongoing studies on crizanlizumab continue to investigate its safety and efficacy.…”

Crizanlizumab

“…Median time to first vaso-occlusive crises after treatment discontinuation was 6.1 months in the high-dose crizanlizumab-tmca group, 2.7 months in the low-dose crizanlizumab-tmca group, and 2.6 months in the placebo group. 14 Limitations: The study lacks long-term data and data in patients younger than 16 years. Several ongoing studies have been initiated to further assess crizanlizumab-tmca.…”