Report by Gensciences during ISTH 2024:

Ø    FRSW107

Title: 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

Presenting author: Feng Xue, Hospital of Hematology, Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), Tianjin, China

Synopsis No.: OC 40.1

Presentation method: Keynote speech at the plenary meeting

Report time: 14:45-15:00 ICT, Monday, June 24, 2024

Full text of synopsis:

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

Title: 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

Presenting author: Mankai Ju, Hospital of Hematology, Chinese Academy of Medical Sciences (Institute of Hematology, Chinese Academy of Medical Sciences), Tianjin, China

Synopsis No.: OC 21.5

Presentation method: Oral

Report time: 15:45-16:00 ICT, Sunday, June23, 2024

Full text of synopsis:

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

Title:  The in vitro and in vivo hemostatic efficacies of a novel FVIIIa-mimetic bispecific antibody, SS315, for the treatment of Hemophilia A.

Presenting author: Weichuan Mo, Beijing Gensciences Inc., Beijing, China

Synopsis No.: OC 21.3

Presentation method: Oral

Report time: 15:15-15:30 ICT, Sunday, June23, 2024

Full text of synopsis:

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.

About Zhongningbei^® (FRSW107)

Zhongningbei®(FRSW107)  is the first double chain coagulation factor VIII-Fc fusion protein of“homodimeric” structure with coagulation activity using an innovative rigid linker technology, which not only extends the half-life of coagulation factor VIII but also improves the product's stability and capacity.Zhongningbei®(FRSW107) is expected to be the first home-made long-acting recombinant factor VIII product that meets the frequency of “two doses a week” in adult and adolescent patients. The product’s core technology has been patented in many countries including China, the United States, and Japan, establishing a high technological barrier.

About SS109

SS109 is the world’s first ultra-long-acting recombinant factor VII product, and has been subjected to Phase II clinical trials in China. It has been demonstrated to have a significantly prolonged half-life, a higher one-injection hemostasis rate and potential safety benefits in head-to-head comparisons with Novoseven.

About SS315

SS315 is a 90-factor bispecific antibody with independent intellectual property rights, mainly used for the prevention and treatment of hemophilia A.

About Gensciences

Founded in 2019 ，Gensciences is a China-based, globally oriented innovative pharmaceutical company for hemophilia. Relying on our leading long-acting biotechnology platform, we focus on the unmet clinical needs of patients with hemophilia and continue to iteratively develop hemophilia drugs with Global Best-In-Class potential，aiming to help hemophilia patients return to a normal life.

Gensciences has four innovative drugs under clinical development and registration review at present.FRSW107 is the first long-acting recombinant coagulation factor VIII product in China and is currently under registration review.SS117 is the second global once-a-week ultra-long-acting recombinant coagulation factor VIII product and it is currently in the Phase III clinical preparation stage.SS109 is the world’s first ultra-long-acting recombinant activated factor VII product. Subjects in its Phase II clinical trial have completed the study and a Phase III clinical protocol is being discussed. SS327 is the world’s first ultra-long-acting recombinant coagulation factor IX product and has been approved for clinical trial in China. In the future, we will focus on developing longer-acting and safer bio-innovative drugs in the field of coagulation and metabolic diseases.