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

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.

Fundamentals and Catalytic Innovation: The Statistical and Data Management Center of the Antibacterial Resistance Leadership Group.

The Statistical and Data Management Center (SDMC) provides the Antibacterial Resistance Leadership Group (ARLG) with statistical and data management expertise to advance the ARLG research agenda. The SDMC is active at all stages of a study, including design; data collection and monitoring; data analyses and archival; and publication of study results. The SDMC enhances the scientific integrity of ARLG studies through the development and implementation of innovative and practical statistical methodologies and by educating research colleagues regarding the application of clinical trial fundamentals. This article summarizes the challenges and roles, as well as the innovative contributions in the design, monitoring, and analyses of clinical trials and diagnostic studies, of the ARLG SDMC.