晟斯生物是一家聚焦于血友病的創新藥公司，近日宣布將于2024年6月22日至26日在泰國曼谷舉行的2024年第32屆國際血栓與止血大會（ISTH）上展示血友病治療研發管線新數據。ISTH會議是全球學術影響力最大的聚焦于血栓與止血領域的國際性會議，晟斯生物本次申報的3篇摘要全部被ISTH 2024接受并將進行口頭報告，其中重凝貝?（FRSW107）的三期臨床數據入選全體大會主旨演講。
晟斯生物在ISTH 2024期間的報告：
? FRSW107
標題： 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
匯報作者：薛峰，中國醫學科學院血液病醫院（中國醫學科學院血液學研究所），中國天津
摘要編號：OC 40.1
報告形式：全體會議主旨演講
報告時間：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.
? SS109
標題： 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
匯報作者：鞠滿凱，中國醫學科學院血液病醫院（中國醫學科學院血液學研究所），中國天津
摘要編號：OC 21.5
報告形式：口頭報告
報告時間：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.
? SS315
標題： The in vitro and in vivo hemostatic efficacies of a novel FVIIIa-mimetic bispecific antibody, SS315, for the treatment of Hemophilia A.
匯報作者：莫煒川，北京基科晟斯醫藥科技有限公司，中國北京
摘要編號：OC 21.3
報告形式：口頭報告
報告時間：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.
關于重凝貝?（FRSW107）
重凝貝?（FRSW107）采用獨創的剛性linker技術，首次獲得了有凝血活性的“同源二聚”結構的雙頭凝血八因子-Fc融合蛋白，在延長八因子半衰期的同時，顯著提高了產品的穩定性和產能。重凝貝?（FRSW107）有望成為首款國產長效重組八因子產品，在成人和青少年患者中能夠滿足“一周兩次”的給藥頻率，其產品核心專利已在中國、美國、日本等多國獲得授權，且具備極高的技術壁壘。
關于SS109
SS109是全球第一款超長效重組七因子，目前在中國已經完成二期臨床實驗，在與諾其的頭對頭比較中證明了明顯延長的半衰期，并展現了更高的一針止血率以及潛在的安全優勢。
關于SS315
SS315是一款具有獨立知識產權的九十因子雙特異性抗體，主要用于血友病A的預防治療。
關于晟斯生物
晟斯生物成立于2019年，是一家立足中國、面向全球的血友病創新藥公司。我們依托領先的長效化生物技術平臺，聚焦于血友病領域病人的未滿足需求，不斷迭代研發具有全球最佳潛力（Global Best-In-Class）的血友病藥物。我們希望能夠通過我們的藥物，幫助血友病患者回歸正常生活。
晟斯生物目前已經有四款創新藥進入臨床開發和注冊審評階段。重凝貝?（FRSW107）是我國第一款長效重組八因子，目前在注冊審評階段。SS117是全球第二款一周一次的超長效重組八因子，目前在三期臨床階段。SS109是全球第一款超長效重組活化七因子，二期臨床試驗入組者完成出組，正在討論三期臨床方案。SS327是全球第一款超長效重組九因子，已經在中國獲批臨床試驗許可。
