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晟斯生物是一家聚焦于血友病的创新药公司，近日宣布将于2024年6月22日至26日在泰国曼谷举行的2024年第32届国际血栓与止血大会（ISTH）上展示血友病治疗研发管线新数据。ISTH会议是全球学术影响力最大的聚焦于血栓与止血领域的国际性会议，晟斯生物本次申报的3篇摘要全部被ISTH 2024接受并将进行口头报告，其中重凝贝®（FRSW107）的三期临床数据入选全体大会主旨演讲。 |
晟斯生物在ISTH 2024期间的报告：
Ø FRSW107
标题：A Novel Extended half-life factor VIII Fc fusion protein FRSW107 for severe hemophilia A: A multicentre, open-label, single-arm, phase 3 study and its open-label extension
汇报作者：薛峰，中国医学科学院血液病医院（中国医学科学院血液学研究所），中国天津
摘要编号：OC 40.1
报告形式：全体会议主旨演讲
报告时间：14:45-15:00 ICT, Monday, June 24, 2024
摘要全文：
Background: Hemophilia A is a rare hereditary disease caused by a deficiency of coagulation factor VIII (FVIII).
Aims: This multicentre, open-label, single-arm phase 3 trial and its open-label extension aimed to assess the efficacy and safety of a novel extended half-life factor VIII (FVIII) Fc fusion protein FRSW107 as prophylactic and on-demand treatment for severe hemophilia A.
Methods: Between October 9, 2020 and June 26, 2022, adolescents and adults with severe haemophilia A (FVIII activities < 1 IU/dL) without FVIII inhibitors received intravenously FRSW107 50 IU/kg Q3D for 50 exposure days and at least six months for prophylaxis or FRSW107 30 to 50 IU/kg for six months for on-demand therapy. The primary outcomes were the annualized bleeding rate (ABR), annualized joint bleeding rate (AJBR) and number of target joints.
Results: Eighty-three patients received prophylaxis and 36 received on-demand treatment; 101 entered the extension period. FRSW107 had a mean elimination half-life of 20.1±4.7 h and a mean incremental recovery of 2.1±0.5 IU/dL/IU/kg. By exposure day 100, 53 (63.9%) patients in the prophylaxis group had zero bleed. The mean ABR was 1.5 ± 3.8 events (95% CI, 1.0-2.3), with a 95.3% reduction from baseline (p < 0.0001). The mean AJBR was 1.2±3.5 events (95% CI, 0.8-1.9), with a 95.8% reduction from baseline (p < 0.0001). The mean number of target joints was 0.1±0.3 (95% CI, 0.0-0.1), representing a 96.9% reduction from baseline (p < 0.0001). Treatment-related adverse events occurred in 19 (16.0%) patients but caused no treatment interruption, discontinuation, withdrawal or death.
Conclusion(s): FRSW107 was well tolerated and efficacious in the prophylactic and episodic treatment of bleeding events in previously treated adolescents and adults with severe hemophilia A.
Ø SS109
标题：An Open-label, Dose-Escalation, Multicenter Phase I Study to Evaluate the Safety, Immunogenicity, and Pharmacokinetics/pharmacodynamics（PK/PD）of Single Dose SS109 in Hemophilia A/B patients with Inhibitor
汇报作者：鞠满凯，中国医学科学院血液病医院（中国医学科学院血液学研究所），中国天津
摘要编号：OC 21.5
报告形式：口头报告
报告时间：15:45-16:00 ICT, Sunday, June23, 2024
摘要全文：
Background: Bleeding episodes (BEs) in hemophilia patients with inhibitors require the administration of bypassing agents such as activated recombinant human factor VII (rhFVIIa). SS109 is a long-acting rhFVIIa-Fc fusion protein. Nonclinical studies showed that the hemostasis of SS109 is better than that of NovoSeven® in same dose, and half-life is 2.5 times longer than that of NovoSeven® in cynomolgus monkeys.
Aims: To evaluate the safety, immunogenicity, and PK/PD characteristics of single-dose SS109 in hemophilia (FVIII activity ≤1% or FIX activity ≤2%) patients with inhibitors.
Methods: In this first-in-human, open-label, dose-escalation, multi-center study, 27 male patients aged 18-65 years were enrolled. Five doses of SS109 (30, 60, 120, 240, and 360 μg/kg) were examined, and the safety, immunogenicity, and PK/PD were evaluated. This study received approval by each site’s IEC/IRB and written informed consents were obtained from all patients.
Results: Single dose of SS109 at all 5 doses was well-tolerated. Two adverse events occurred in 2 patients (7.4%) were possibly related to SS109. No hypersensitivity or allergic reactions occurred. Table 1 summarizes the baseline-corrected FVII activity PK parameters of SS109. Both the Cmax and the AUC were dose dependent across 5-dose level, with linear dose proportionality being observed within the dose range from 120 to 360μg/kg (Figure 1). The mean half-life ranged from 9.5 hours to14.5 hours, 3 to 7-fold longer than that of NovoSeven®. The aPTT and PT in patients were immediately shortened but returned to the baseline level around 24h and between 48h and 72h, respectively. The maximum reduction (∆Emax) of PT and aPTT after SS109 administration are shown in Table1.
Conclusion(s): This study demonstrated that SS109, a long-acting rhFVIIa-Fc, was well-tolerated and had dose-dependent PK/PD characteristics that support further assessment of its potential hemostasis efficacy in BEs in hemophilia patients with inhibitors.
Ø SS315
标题：The in vitro and in vivo hemostatic efficacies of a novel FVIIIa-mimetic bispecific antibody, SS315, for the treatment of Hemophilia A.
汇报作者：莫炜川，北京基科晟斯医药科技有限公司，中国北京
摘要编号：OC 21.3
报告形式：口头报告
报告时间：15:15-15:30 ICT, Sunday, June23, 2024
摘要全文：
Background: Hemophilia A (HA) is a genetic disorder characterized by factor VIII (FVIII) deficiency. A non-factor therapeutic, FVIIIa-mimetic bispecific antibody (BsAb) Emicizumab, was marketed worldwide including China for the treatment of HA. However, due to cost, it is not available for the majority Chinese patients. We have developed a novel symmetric FVIIIa-mimetic BsAb, SS315, by targeting FX with its upper Fab arms and FIXa with its down-side scFv arms, respectively, enhancing the catalyzing efficiency of FIXa and being functional at low concentration ranges, which could address a significant unmet clinic need for the HA patients in the developing countries.
Aims: To demonstrate the hemostatic potency of SS315 in vitro and in vivo.
Methods: The affinity was identified by bio-layer interferometry. The coagulation potency was measured by FXIa-activated thrombin generation assay. The hemorrhage-preventing capacity was examined by tail vein transection test in the FIX- and FX-humanized HA mice model. The hemostasis capacity was confirmed in FVIII-neutralizing antibody-induced acquired HA (AHA) Cynomolgus monkeys.
Results: The affinities of SS315 to hFIXa and hFX were < 1 nM. SS315 exhibited dose advantage over Emicizumab in hemostatic potency at low concentrations. Multiple intravenous doses of SS315 (0.25 - 8 mg/kg) effectively prevented bleeding in HA mice (Fig. 1C). Low doses of SS315 (0.5 - 1.0 mg/kg) achieves similar hemostatic effect with 3.0 mg/kg Emicizumab, suggesting a superior potency of SS315 over Emicizumab in vivo. Moreover, it was confirmed that low doses of SS315 (0.5 and 2.0 mg/kg) shortened activated partial thromboplastin time and reduced blood losses and bleeding times, achieving comparable efficacy of 3.0 mg/kg Emicizumab in AHA monkeys.
Conclusion(s): Combining in vitro and HA/AHA animal models, the present study supports that SS315 can mimic the activity of FVIIIa to control bleeding and has a better pharmacologic profile than Emicizumab.
关于重凝贝®（FRSW107）
重凝贝®（FRSW107）采用独创的刚性linker技术，首次获得了有凝血活性的“同源二聚”结构的双头凝血八因子-Fc融合蛋白，在延长八因子半衰期的同时，显著提高了产品的稳定性和产能。重凝贝®（FRSW107）有望成为首款国产长效重组八因子产品，在成人和青少年患者中能够满足“一周两次”的给药频率，其产品核心专利已在中国、美国、日本等多国获得授权，且具备极高的技术壁垒。
关于SS109
SS109是全球第一款超长效重组七因子，目前在中国已经完成二期临床实验，在与诺其的头对头比较中证明了明显延长的半衰期，并展现了更高的一针止血率以及潜在的安全优势。
关于SS315
SS315是一款具有独立知识产权的九十因子双特异性抗体，主要用于血友病A的预防治疗。
关于晟斯生物
晟斯生物成立于2019年，是一家立足中国、面向全球的血友病创新药公司。我们依托领先的长效化生物技术平台，聚焦于血友病领域病人的未满足需求，不断迭代研发具有全球最佳潜力（Global Best-In-Class）的血友病药物。我们希望能够通过我们的药物，帮助血友病患者回归正常生活。
晟斯生物目前已经有四款创新药进入临床开发和注册审评阶段。重凝贝®（FRSW107）是我国第一款长效重组八因子，目前在注册审评阶段。SS117是全球第二款一周一次的超长效重组八因子，目前在三期临床阶段。SS109是全球第一款超长效重组活化七因子，二期临床试验入组者完成出组，正在讨论三期临床方案。SS327是全球第一款超长效重组九因子，已经在中国获批临床试验许可。