First-in-human pharmacokinetic, safety, and preliminary efficacy studies of single- and multiple-dose FRSW117, a novel PEGylated recombinant factor VIII-Fc fusion protein with an extended half-life, in patients with severe hemophilia A

The treatment for severe hemophilia A involves exogenous factor VIII (FVIII) replacement, but the utilization of prophylactic treatment in China remains limited, at just 16.2% of patients, lower than the rates observed in developed nations.^1,2 The traditional goal of prophylaxis in hemophilia A is to sustain FVIII activity levels above 1 IU/dL (1%).³ Attaining these elevated trough levels using standard half-life recombinant FVIII products remains challenging, necessitating frequent injections. Extended half-life FVIII products offer a longer duration of action,⁴ mostly with biweekly injections. Notably, efanesoctocog alfa has a half-life of approximately 40 hours,⁵ enabling weekly prophylactic injections. The choice of extended half-life FVIII products is limited in China, so far.

FRSW117 is the first pegylated recombinant FVIII-Fc fusion protein manufactured by random pegylation of recombinant human FVIII-Fc fusion protein. In preclinical studies, FRSW117 exhibited an extended half-life of 37 hours at a dose of 125 IU/kg in Cynomolgus monkeys, surpassing the 4.69-hour half-life of Xyntha®, and demonstrated comparable procoagulant activity, superior prophylactic efficacy, and a manageable safety profile (unpublished data). Here, we report results from two studies: a phase I first-in-human trial (NCT04864743) examining the safety and pharmacokinetics of FRSW117 in comparison with those of Advate® and a phase II study (NCT05265286) assessing the pharmacokinetics, safety, and initial efficacy of a repeated four-dose regimen of FRSW117, administered weekly in patients with severe hemophilia A (FVIII activity <1%) who had undergone previous treatment with FVIII for ≥150 exposure days. Informed consent was obtained from all patients and protocols were approved by the ethics committee of the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (phase I: XY2021018-EC-1; phase II: XY2022002-EC-1) and other participating centers.

In the phase I study, the participants in the 25 IU/kg cohort received Advate® and then the same dose of FRSW117 at a 4-day interval. FVIII activity was measured over 72 hours for Advate® and 216 hours for FRSW117. Upon confirming the safety and tolerance of FRSW117 in three participants, enrollment continued for the 25 and 50 IU/kg dose cohorts (N ≥6/cohort). In the multicenter, open-label phase II study, the participants were enrolled into the 40 and 50 IU/kg cohorts (N ≥6/cohort) and received FRSW117 on days 1, 8, 15, and 22. If bleeding episodes occurred after the second and before the third FRSW117 injection, the drug was administered for breakthrough bleeding treatment determined by investigators according to guidelines and individual patients’ needs.³ The safety and tolerability were judged by the investigators via detection of adverse events (AE), anti-drug antibodies (ADA) and FVIII inhibitors. The preliminary efficacy of FRSW117 was evaluated in the phase II trial. The follow-up was until 28 days after the single dose and the dose on day 22 in the phase I and phase II study, respectively. For the statistical analyses, SAS 9.4 (SAS Institute Inc., Cary, NC, USA) was employed. Pharmacokinetic parameters were deduced through a non-compartmental analysis method using Phoenix WinNonlin 8.3.

In the phase I study, there were six and seven participants in the 25 and 50 IU/kg cohorts, respectively. Before the study, 53.8% (7 participants) received on-demand FVIII treatment (Table 1). All 13 participants completed the study. Peak serum concentration (Cmax) and area under the con- centration curve (AUC_0-∞) increased in a dose-dependent manner. The geometric mean elimination half-life (t_1/2) of FRSW117 was more than twice that of Advate®, being 28.4 versus 13.3 hours in the 25 IU/kg cohort and 30.8 versus 13.8 hours in the 50 IU/kg cohort, respectively (Table 2). The time to 3% and 1% FVIII activity for FRSW117 was longer, approximately 2.5 times that with Advate® (25 IU/kg cohort: 121.633 and 169.566 hours; 50 IU/kg cohort: 165.147 and 206.462 hours). The AUC₀-_∞ for FVIII activity over time with FRSW117 was more than triple that of Advate® for the corresponding doses (Table 2). The geometric mean incremental recovery of FRSW117 was 2.955 ([IU/dL]/[IU/ kg]) in the 25 IU/kg cohort and 2.637 ([IU/dL]/[IU/kg]) in the 50 IU/kg cohort. Nine participants (69.2%) experienced 18 treatment-emergent AE, all grade 1 or 2 (Online Supplementary Table S1). Among these, five treatment-emergent AE in three participants (23.1%) were FRSW117-related. There were no serious AE or AE leading to discontinuation of the study drug. No FVIII inhibitors were detected. Four out of 13 participants developed ADA; two were identified as pre-existing, and two occurred after dosing (but it was not known whether these cases were due to Advate^® or FRSW117). The participants did not exhibit spontaneous bleeding episodes for 168 hours following a single dose of FRSW117 (both dosages). One traumatic joint bleeding episode due to an ankle sprain was reported in a patient in the 50 IU/kg cohort 3 days after FRSW117 administration (resolved with two doses of recombinant activated factor factor VII to avoid interference with the pharmacokinetic analysis and FVIII activity measurements).

Table 1.Demographic and clinical characteristics of the participants at baseline.

The phase II study enrolled eight and seven participants in the 40 and 50 IU/kg groups, respectively (Table 1). Fourteen participants completed the study. The mean FVIII activity exceeded 10% at 96 hours after dosing. At 168 hours, the activity levels were 3.25% and 2.88%, respectively (Online Supplementary Table S2). At steady-state, the geometric mean elimination t_1/2 was 33.0 hours for the 40 IU/kg cohort and 37.2 hours for the 50 IU/kg cohort, suggesting a dose-proportional trend of C_max and AUC_0-t (Table 3). Ten participants (66.7%) experienced 20 treatment-emergent AE. All these treatment-emergent AE were grade 1 or 2 (Online Supplementary Table S3). There were no serious AE or AE leading to treatment discontinuation in the study. No FVIII inhibitors were detected. Four participants (26.7%) had at least one positive ADA result but these were identified as pre-existing. Three participants had pre-existing anti-PEG antibodies of the IgM subtype, and two had pre-existing anti-PEG antibodies of the IgG subtype. None of these anti-PEG antibodies was induced or emerged due to the treatment. Twelve (80%) participants did not experience bleeding episodes. In the 40 IU/kg cohort, there was one spontaneous joint bleed (6.67%) 130.65 hours after the last FRSW117 administration and one traumatic oral bleed due to brushing teeth. Both bleeds resolved with one dose of FRSW117 (average dose: 30.01 ± 0.008 IU/kg). The response rate (excellent + good) was 100%. No spontaneous bleeding episodes were observed in the 50 IU/kg cohort. One subject in the 50 IU/kg cohort reported three instances of traumatic oral bleeding due to brushing teeth and one case of oral bleeding due to pericoronitis.

The pharmacokinetic findings from our phase I and II clinical studies of FRSW117 underscore a pivotal advancement in hemophilia A treatment, highlighting its ultra-long half-life and potential to reduce prophylactic infusion frequency. Notably, the t_1/2 of FRSW117 after single doses of 25 and 50 IU/kg was 28.4 and 30.8 hours, respectively. Comparatively, FRSW117 exhibits a longer t_1/2 than twice-weekly extended half-life products, such as efmoroctocog alfa (19.0 hours), rurioctocog alfa pegol (16.0 hours), damoctocog alfa pegol (17.0 hours), and turoctocog alfa pegol (16 hours),^6-8 yet falls short of the t_1/2 reported for efanesoctocog alfa (40 hours).^5,9 By potentially reducing the frequency of prophylactic infusions, FRSW117 would probably offer a promising avenue for improving the therapeutic landscape for patients, contingent upon further validation in future trials.

The study’s findings on C_max and incremental recovery rate underscore the comparable hemostatic efficacy of FRSW117 to that of standard half-life products. Despite slight variations in C_max between FRSW117 and Advate^®, the ratios indicate substantial equivalence, reinforcing the therapeutic potential of FRSW117 in achieving desired hemostatic levels with a reduced dosing frequency. This equivalence in peak plasma concentration and incremental recovery, pivotal for effective hemostasis, aligns with previous research.¹⁰ Targeting trough levels exceeding 3%, as suggested by emerging preferences in clinical practice, could potentially optimize prophylaxis by reducing bleeding episodes and enhancing patients’ quality of life,³ corroborated by the findings of the PROPEL trial.¹¹ Furthermore, the relationship between FVIII exposure and bleeding frequency, is highlighted in the analysis of the LEOPOLD,¹² A-LONG, and Kids A-LONG^8,13 trials and real-world studies.¹⁴ Taken together, FRSW117 may offer a viable alternative in managing severe hemophilia A, combining efficacy with enhanced patients’ convenience. FRSW117 demonstrated low potential for inducing neutralizing antibodies against FVIII. The absence of FVIII inhibitor development in all participants may suggest the safety of FRSW117 in the context of immunogenicity. Although there were instances of ADA and anti-PEG antibodies, their titers were lower than 1:80. The immunogenicity of FRSW117 was favorable,¹⁵ although this will have to be confirmed in the context of multiple doses over a longer period since the present study lasted 28 days. Nevertheless, those results may add a layer of confidence in using PEGylation technology for hemophilia A treatment.

Table 2.Pharmacokinetic parameters of the single-dose phase I pharmacokinetic study and comparison between Advate® and FRSW117.

Table 3.Pharmacokinetic parameters of multiple doses of FRSW117.

We acknowledge that these studies had inherent limitations, including a small cohort of participants reflective of its early-phase design focused primarily on pharmacokinetics and safety assessments. The study duration was too short to calculate annualized bleeding rates. Consequently, the long-term prophylactic efficacy and safety profiles of FRSW117 remain to be thoroughly evaluated.

In conclusion, the two studies of FRSW117 suggest the safety and tolerability of this very long half-life FVIII product over a 4-week treatment duration, alongside superior pharmacokinetics compared with those of standard half-life recombinant FVIII. These insights advocate for the potential of FRSW117 to confer extended bleeding protection with reduced dosing frequency, underscoring the need for its development. A pivotal phase III study is ongoing in China (NCT06142552).

Footnotes

• Received January 15, 2025
• Accepted May 30, 2025

Correspondence

R. YANG - rcyang@ihcams.ac.cn

Disclosures

No conflicts of interest to disclose.

Contributions

Funding

The two studies, as well as medical writing assistance for this manuscript, were funded by Gensciences.

Acknowledgments

Medical writing assistance for the development of this manuscript, under the direction of the authors, was provided by Shanghai Medsci Medical Technology Co., Ltd. Statistical analysis was provided by Shanghai Bestudy Medical Technology Co. Ltd. and biomarker testing was provided by Shanghai Dingyue Biotechnology Co. Ltd.