PMID- 31778283 OWN - NLM STAT- MEDLINE DCOM- 20201001 LR - 20210110 IS - 1365-2516 (Electronic) IS - 1351-8216 (Print) IS - 1351-8216 (Linking) VI - 26 IP - 1 DP - 2020 Jan TI - SHP656, a polysialylated recombinant factor VIII (PSA-rFVIII): First-in-human study evaluating safety, tolerability and pharmacokinetics in patients with severe haemophilia A. PG - 47-55 LID - 10.1111/hae.13878 [doi] AB - 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. CI - (c) 2019 The Authors. Haemophilia published by John Wiley & Sons Ltd. FAU - Tiede, Andreas AU - Tiede A AUID- ORCID: 0000-0002-3600-8536 AD - Hannover Medical School, Hannover, Germany. FAU - Allen, Geoffrey AU - Allen G AUID- ORCID: 0000-0003-4351-1014 AD - Baxalta US Inc, a member of the Takeda group of companies, Cambridge, MA, USA. FAU - Bauer, Alexander AU - Bauer A AD - Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria. FAU - Chowdary, Pratima AU - Chowdary P AUID- ORCID: 0000-0002-6690-8586 AD - Katharine Dormandy Haemophilia and Thrombosis Centre, Royal Free Hospital, London, UK. FAU - Collins, Peter AU - Collins P AD - Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK. FAU - Goldstein, Brahm AU - Goldstein B AD - Baxalta US Inc, a member of the Takeda group of companies, Cambridge, MA, USA. FAU - Jiang, Hongyu Jeanne AU - Jiang HJ AD - Baxalta US Inc, a member of the Takeda group of companies, Cambridge, MA, USA. FAU - Kӧck, Kathleen AU - Kӧck K AD - IQVIA, Overland Park, KS, USA. FAU - Takacs, Istvan AU - Takacs I AD - Semmelweis University, Budapest, Hungary. FAU - Timofeeva, Margarita AU - Timofeeva M AD - Federal State Budgetary Institution of Science "Kirov Scientific and Research Institute of Hematology and Blood Transfusion of Federal Medico-Biological Agency", Kirov, Russian Federation. FAU - Wolfsegger, Martin AU - Wolfsegger M AD - Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria. FAU - Srivastava, Shouryadeep AU - Srivastava S AD - Baxalta US Inc, a member of the Takeda group of companies, Cambridge, MA, USA. LA - eng SI - ClinicalTrials.gov/NCT02716194 GR - Baxalta US Inc, a member of the Takeda group of companies/ PT - Clinical Trial, Phase I PT - Journal Article PT - Multicenter Study DEP - 20191128 PL - England TA - Haemophilia JT - Haemophilia : the official journal of the World Federation of Hemophilia JID - 9442916 RN - 0 (Recombinant Proteins) RN - 0 (Sialic Acids) RN - 0 (polysialic acid) RN - 9001-27-8 (Factor VIII) SB - IM MH - Adult MH - Factor VIII/adverse effects/immunology/*pharmacokinetics/*therapeutic use MH - Hemophilia A/*drug therapy MH - Humans MH - Recombinant Proteins/*therapeutic use MH - Sialic Acids/*chemistry PMC - PMC7027936 OTO - NOTNLM OT - haemophilia A OT - pharmacokinetics OT - polysialic acid OT - recombinant FVIII OT - safety OT - tolerability COIS- 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. EDAT- 2019/11/30 06:00 MHDA- 2020/10/02 06:00 PMCR- 2020/02/18 CRDT- 2019/11/29 06:00 PHST- 2019/07/05 00:00 [received] PHST- 2019/10/11 00:00 [revised] PHST- 2019/10/22 00:00 [accepted] PHST- 2019/11/30 06:00 [pubmed] PHST- 2020/10/02 06:00 [medline] PHST- 2019/11/29 06:00 [entrez] PHST- 2020/02/18 00:00 [pmc-release] AID - HAE13878 [pii] AID - 10.1111/hae.13878 [doi] PST - ppublish SO - Haemophilia. 2020 Jan;26(1):47-55. doi: 10.1111/hae.13878. Epub 2019 Nov 28.