-Author name in bold denotes the presenting author
-Asterisk * with author name denotes a Non-ASH member
Clinically Relevant Abstract denotes an abstract that is clinically relevant.

PhD Trainee denotes that this is a recommended PHD Trainee Session.

Ticketed Session denotes that this is a ticketed session.

2615 Pharmacokinetics, Safety and Preliminary Efficacy of Multiple Doses of Pegylated Recombinant Human Coagulation Factor VIII-Fc Fusion Protein (FRSW117) in Previously Treated Adult and Adolescent Subjects with Severe Hemophilia a: Results from an Open-Label, Multicenter, Phase 2 Study

Program: Oral and Poster Abstracts
Session: 322. Disorders of Coagulation or Fibrinolysis: Clinical and Epidemiological: Poster II
Hematology Disease Topics & Pathways:
Research, clinical trials, Bleeding and Clotting, adult, Clinical Research, drug development, Diseases, Therapies, Study Population, Human
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Feng Xue, MD1*, Weizhi Chen2*, Shuxia Guo, MD3*, Haiying Hua, MD4*, Yu Cao5*, Xianqi Feng5* and Renchi Yang, MD1

1Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
2People’s Hospital of Rizhao, Rizhao, China
3Zhengzhou People's Hospital, Zhengzhou, CHN
4Affiliated Hospital of Jiangnan University, Jiangsu, CHN
5Affiliated Hospital of Qingdao University, qingdao, China

IntroductionProphylaxis of severe hemophilia A (HA) with standard half-life Factor VIII (FVIII) products necessitates frequent administration, and low trough FVIII activity levels lead to higher risk of bleeds. FRSW117 is a PEGylated recombinant human coagulation factor VIII Fc fusion protein (PEGylated rhFVIII-Fc), in a phase 1 study, single-dose FRSW117 was well tolerated and provided a prominently longer t1/2 with FVIII activity maintaining at ≥ 1% for more than 7 days.

This open-label, multicenter phase 2 study (NCT05265286) aimed to evaluate the PK, safety, and preliminary efficacy of multiple 4 doses of FRSW117 in previously treated subjects with severe HA.

MethodsSevere HA (FVIII:C <1%) patients aged 12 (inclusive) to 65 years, previously treated with FVIII products 150 exposure days (EDs) were enrolled in two cohorts (M1, 40IU/kg; M2, 50IU/kg), to receive 4 once-weekly doses of FRSW117 on day 1, 8, 15, and 22 (ED1 to ED4), respectively. The PK characteristics, safety, and immunogenicity of FRSW117 were evaluated. PK samples were collected pre-dose on day 1, 8, 15, 22, and at multiple times after infusion on day 1 and day 22.

The primary endpoints were the PK parameters, the occurs of AEs, inhibitor development, and other immunogenicity profiles; the secondary endpoints were the bleeding episodes during multiple dosing. FVIII activity was determined using one-stage clotting assay. FVIII inhibitor was tested using the Nijmegen-modified Bethesda assay. PK analyses were performed using noncompartmental analysis (Phoenix WinNonlin 8.3).

ResultsBetween April 2022 and August 2022, a total of 15 male subjects were enrolled in cohort M1 (N=8) and M2 (N=7). 13/15 (86.7%) of the subjects were adults, 2 of them were adolescent, both in M1. The mean age was 28.1 (range: 13, 44) in M1 and 30.6 (range: 23, 36) in M2. 14 subjects completed the study, with 1 subject in M2 withdrew early after the PK sampling of ED1 due to personal reasons.

Baseline-corrected PK parameters were summarized in Table 1. Geometric mean elimination half-life (t1/2) of M1 and M2 were 29.536h and 31.545 h, respectively, consisting with the first-in-human single dose study. Area under the activity-time curve (AUC0-t), and steady-state maximum concentration (Cmax) after 4 weekly doses for M1 and M2 were 4557.1 and 4937.9 h*IU/dL, 101.26 and 122.76 IU/dL, respectively. The mean FVIII activity at 168h after dose for M1 and M2 were summarized in Table 2, and it were 3.25 and 2.88 IU/dL on 168 h (7 day) after the dose on D22. Baseline-corrected FVIII activity over time of 2 cohorts are shown in Figure 1. The accumulation index based on AUCtau were 1.008 and 1.098, respectively, indicating there was minimal accumulation after 4 once-weekly doses.

A total of 10 (66.7%,10/15) subjects reported 20 treatment emergent adverse events (TEAE) during the study. No ≥ grade 3 adverse events, serious adverse events (SAE), adverse event leading to treatment discontinuation, or AESI were reported.

No positive FVIII inhibitor was detected during the study. Pre-existing Anti-PEG-rhFVIII-Fc antibodies (ADA) were observed in 4/15 (26.7%) subjects.Pre-existing anti-PEG antibodies were observed in 3/15 (20.0%) subjects. No treatment emergent ADA and anti-PEG antibodies were observed, no treatment-boost ADA and anti-PEG antibodies were observed in subjects with pre-existing ADA and anti-PEG antibodies. No significant impact of pre-existing ADA and/or anti-PEG antibodies on PK variable, safety profile and preliminary efficacy was observed.

12/15 (80.0%) patients experienced zero bleeding episodes during the 4-week FRSW117 treatment period (from day 1 through day 28, 7 days after D22 dosing). Three of 15 (20.0%) subjects experienced 6 bleeding events among which only 1 spontaneous bleeding episode in cohort M1. 2 bleeds episodes were treated with FRSW117 of mean dose of 30.01 IU/kg and both were controlled after one infusion, with a hemostatic response rate of 100%.

Conclusion: The therapy of 4 once-weekly doses of FRSW117 displayed favorable safety profile and provided about 3% mean FVIII activity on day 7 postdose with minimal accumulation. These results suggest that FRSW117 may offer extended bleeding protection with weekly dose interval and support further assessment of FRSW117 in phase 3 study.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH