SHP656, a polysialylated recombinant factor VIII (PSA‐rFVIII): First‐in‐human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A

Abstract

Introduction: SHP656 is the first factor VIII (FVIII) product developed using polysialylation (PSA) technology, in which full-length recombinant (r) FVIII (anti-haemophilic factor [recombinant]) is conjugated with a 20 kDa PSA polymer.Aim: To compare the safety, immunogenicity and pharmacokinetics of SHP656 vs the parent rFVIII (octocog alfa) after single infusions of 25-75 IU/kg in patients with severe haemophilia A (FVIII activity <1%).Methods: Multinational, phase 1, prospective, open-label, two-period, fixed-sequence, dose-escalation trial (clinicaltrials.gov NCT02716194). Patients received single doses of rFVIII and then SHP656 sequentially at the same dose: 25 ± 3 IU/kg (Cohort 1), 50 ± 5 IU/kg (Cohort 2) and 75 ± 5 IU/kg (Cohort 3).Results: Forty patients received rFVIII: 11 in Cohort 1, 16 in Cohort 2 and 13 in Cohort 3. Two patients withdrew before receiving SHP656, leaving 38 patients who completed the study and received both treatments. No treatment-related adverse events (AEs), serious AEs, deaths, study withdrawals, thrombotic events or allergic reactions were reported; and no significant treatment-related changes in laboratory parameters or vital signs. No patients developed FVIII inhibitors or antibodies to PSA. FVIII activity was significantly prolonged following SHP656 administration vs rFVIII with an approximately 1.5-fold extension in mean residence time (P < .05).Exposure increased proportional to the SHP656 dose over the 25-75 IU/kg dose range. Conclusion:Polysialylation of rFVIII confers a half-life extension similar to that of approved extended half-life products that use either PEGylation or Fc fusion technology and was not associated with any treatment-related adverse events. K E Y W O R D Shaemophilia A, pharmacokinetics, polysialic acid, recombinant FVIII, safety, tolerabilityThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

Clot formation and fibrinolysis assays reveal functional differences among hemostatic agents in hemophilia A plasma

“…Supplementary Table S1 shows clinical dosing ranges and concentrations tested. Concentrations of each hemostatic agent were selected to span the plasma concentrations achieved following standard dosing strategies ([ 4 , 7 , 8 , [35] , [36] , [37] , [38] , [39] ] and indicated in Supplementary Table S1 ) and enable curve fitting to identify maximum responses, if possible. Human tissue factor (Dade Innovin) was from Siemens Healthcare Diagnostics.…”

“…rFVIII has an average half-life of ∼12 hours and is given every other day. Other recombinant FVIII products based on the same manufacturing platform are PEGylated (Adynovate) or polysialylated (SHP656, formerly BAX-826 [ 4 ]) to increase their half-life up to ∼1.5-fold versus rFVIII and reduce the need for frequent infusions [ 4 ]. A recombinant B-domainless FVIII construct based on the porcine FVIII sequence (Obizur) has low cross-reactivity with human FVIII inhibitors, which enables administration in patients with inhibitors [ 5 ].…”

A Review of Protein- and Peptide-Based Chemical Conjugates: Past, Present, and Future

“…Polysialic acid is a biodegradable polymer of sialic acid, a component of cell membranes and glycoproteins. A PSA-rhFVIII recently completed Phase 1 clinical trials but was discontinued for lack of efficacy [ 230 ]. HA is an endogeneous polysaccharide that is degraded via hyaluronidases present in many tissues, including in the liver and kidneys.…”

Selective human factor VIII activity measurement after analytical in‐line purification

“…19,20 Recently, a new type of chromogenic assay, termed the modification-dependent activity assay (MDAA), 21 has been developed. This assay enables selective measurement of PEGylated [22][23][24] or polysialylated [25][26][27] recombinant FVIII in the presence of nonmodified FVIII. The MDAA uses a modification-recognizing capturing agent, which currently is an antibody against polyethylene glycol or polysialic acid that selectively binds modified FVIII in the presence of endogenous, nonmodified FVIII.…”