Potency-Adjusted Analyses of a Head-to-Head Pharmacokinetic Study of Damoctocog Alfa Pegol (BAY 94-9027) and Efmoroctocog Alfa (rFVIIIFc) in Patients with Severe Hemophilia A

Background
Damoctocog alfa pegol (BAY 94-9027; Jivi^®) is a B-domain-deleted recombinant factor VIII (FVIII), site-specifically PEGylated with a single, dual-branched 60 kDa polyethylene glycol molecule to extend its half-life. A previous head-to-head crossover study demonstrated that damoctocog alfa pegol has an improved pharmacokinetic (PK) profile compared with efmoroctocog alfa (rFVIIIFc; Elocta^®/Eloctate^®), an extended-half-life (EHL), recombinant FVIII fusion protein. A single infusion of damoctocog alfa pegol resulted in 25% higher area under the curve (AUC_last) and 20% lower clearance (CL) compared with efmoroctocog alfa. Owing to differences in batch-specific FVIII activity, the actual dose of efmoroctocog alfa administered was subsequently found to be higher than for damoctocog alfa pegol. Thus, to provide a more accurate assessment of the differences in PK parameters between these two products, actual dosing should be considered. In the present study, dose-normalized analyses considering the dosing based on actual potency were performed for an accurate and valid comparison of PK parameters between damoctocog alfa pegol and efmoroctocog alfa.

Methods
The head-to-head comparison of the PK of EHL FVIII products was a single-center, randomized, open-label, crossover study of damoctocog alfa pegol and efmoroctocog alfa (ClinicalTrials.gov identifier: NCT03364998). Eligible patients were male, aged 18–65 years with severe hemophilia A (FVIII <1%). After a wash-out period of ≥3 or ≥5 days for prior treatment with standard-half-life or EHL FVIII products respectively, patients were randomized 1:1 to receive a single 60 IU/kg dose of either damoctocog alfa pegol or efmoroctocog alfa. Patients received a single dose of the other product following a ≥7-day wash-out after the dose of the first product. In the study, doses were determined based on the nominal potency value as labeled on the vial. In the present study, PK parameters including normalized AUC (AUC_norm), CL, normalized maximum concentration (C_{max norm}), volume of distribution at steady state (V_ss) and incremental recovery, were assessed using doses adjusted for actual potencies, according to the certificates of analysis provided by the manufacturers for the actual batches used.

Results
As previously described elsewhere, one patient with pre-existing anti-PEG antibodies was considered an outlier for the PK analysis and was excluded from this analysis. In total, 17 patients were included in this analysis, and had a median age of 34 years (Table 1). For both drugs, vials with nominal potency of 1000 IU/vial were used, while actual potencies of efmoroctocog alfa and damoctocog alfa pegol used in this study were 1093 IU/vial and 990 IU/vial, respectively. Hence, the actual dose of efmoroctocog alfa administered was approximately 10.4% higher than the administered dose of damoctocog alfa pegol. After potency-adjustment, AUC_norm and CL were in favor of damoctocog alfa pegol (Table 2). AUC_norm was significantly increased by 39% (P < 0.001) for damoctocog alfa pegol compared with efmoroctocog alfa; an increase with damoctocog alfa pegol compared with efmoroctocog alfa was observed in 16 (94.1%) out of 17 patients. Geometric mean CL was significantly reduced with damoctocog alfa pegol versus efmoroctocog alfa (0.0198 dL/h/kg vs 0.0273 dL/h/kg; P < 0.001), with 16 (94.1%) patients exhibiting a difference in favor of damoctocog alfa pegol. No significant differences in C_{max norm} between the two products were observed.

Conclusion
In the precedent analysis, published elsewhere, damoctocog alfa pegol demonstrated improvements in AUC, CL and t½ compared with efmoroctocog alfa. The improvements are confirmed in this potency-adjusted analysis, while, compared with the unadjusted analysis, a greater improvement for AUC_norm is observed for damoctocog alfa pegol versus efmoroctocog alfa. These data further support the superior PK profile of damoctocog alfa pegol compared with efmoroctocog alfa.