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.

Keywords: haemophilia A; pharmacokinetics; polysialic acid; recombinant FVIII; safety; tolerability.

Conflict of interest statement

AT reports grants and personal fees for lectures and consultancy from Alnylam, Bayer, Biogen Idec, Biotest, Boehringer Ingelheim, Chugai, CSL Behring, Daiichi Sankyo, Leo Pharma, Novo Nordisk, Octapharma, Pfizer, Portola, Roche, Shire*, and Sobi. GA and HJJ are employees of Baxalta US Inc, a member of the Takeda group of companies, Cambridge, MA, USA and stockholders in Takeda Pharmaceutical Company Limited. AB and MW are employees of Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria, and stockholders in Takeda Pharmaceutical Company Limited. PC has received honoraria from Baxalta/Shire*, Biogen Idec, CSL Behring, Novo Nordisk, Pfizer, Roche and Sobi; has served on advisory boards for Bayer, Baxalta/Shire*, Biogen Idec, CSL Behring, Chugai, Freeline, NovoNordisk, Pfizer, Roche, Sanofi and Sobi; and has received research funding from Bayer, CSL Behring, Novo Nordisk, Pfizer and Sobi. P Collins has received support to attend meetings from Shire*, Novo Nordisk and Bayer; and has worked as a paid consultant to Shire*, Bayer, Sobi, Novo Nordisk and Roche. KK is an employee of IQVIA, which received funding from Baxalta US Inc, a member of the Takeda group of companies, Lexington, MA, USA, for the conduction of the study. IT, MT and SS stated that they had no interests which might be perceived as posing a conflict or bias. SS and BG were employees of Baxalta US Inc, now part of Takeda, Cambridge MA, USA at the time of the current study.

© 2019 The Authors. Haemophilia published by John Wiley & Sons Ltd.

Figures

Figure 1

Study design. a6 wk ± 4 d post‐SHP656 infusion. bFollowed by minimum 4‐day (96‐h) washout period (maximum 4 wk) prior to SHP656 infusion. cBlood samples for PK analysis were collected predose and up to 72 h following rFVIII administration and predose and up to 168 h following SHP656 administration. Blood samples for measurement of FVIII activity and FVIII antigen levels were collected at screening, during PK study visits, and at termination visit. Patients were to remain at the study site for 12‐h postinfusion and return the following day for the 24‐hour PK sampling. AE, adverse event; FVIII, factor VIII; PK, pharmacokinetic; rFVIII, recombinant human factor VIII

Figure 2

Median (IQR) preinfusion‐corrected plasma FVIII activity (linear and semi‐logarithmic scales) following infusion of rFVIII and SHP656 at (A) 25, (B) 50 and (C) 75 IU/kg. IQR, inter‐quartile range; FVIII, factor VIII; rFVIII, recombinant factor VIII