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Haemophilia. 2020 Jan;26(1):47-55. doi: 10.1111/hae.13878. Epub 2019 Nov 28.

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

Author information

1
Hannover Medical School, Hannover, Germany.
2
Baxalta US Inc, a member of the Takeda group of companies, Cambridge, MA, USA.
3
Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria.
4
Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK.
5
Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
6
IQVIA, Overland Park, KS, USA.
7
Semmelweis University, Budapest, Hungary.
8
Federal State Budgetary Institution of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of Federal Medico-Biological Agency", Kirov, Russian Federation.

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

PMID:
31778283
DOI:
10.1111/hae.13878
Free PMC Article

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