Pharmacokinetics, immunogenicity, safety, and preliminary efficacy of subcutaneous turoctocog alfa pegol in previously treated patients with severe hemophilia A (alleviate 1)

Abstract

Background: The current standard of care for patients with hemophilia A is regular prophylaxis with factor VIII (FVIII) administered intravenously. Interest in subcutaneous (s.c.) administration, to potentially increase convenience, reduce the treatment burden and improve compliance, is increasing.

Objectives: Evaluate the pharmacokinetics (PK), immunogenicity, safety, and preliminary efficacy of s.c. administration of turoctocog alfa pegol (s.c. N8-GP) in adult or adolescent previously treated patients (PTPs) with severe hemophilia A (alleviate 1; NCT02994407).

Patients/methods: In part A, 24 PTPs received a single dose of s.c. N8-GP (12.5, 25, 50, or 100 IU/kg) with 6 patients per cohort. PK modelling of data from part A supported a suitable dose for part B. Part B comprised a multiple dose trial in 26 PTPs; patients <60 kg received 2000 IU and patients ≥60 kg received 4000 IU s.c. N8-GP daily for 3 months.

Results: Single-dose s.c. N8-GP supported dose linearity. Daily prophylaxis with s.c. N8-GP appeared well tolerated and efficacious, achieving a mean trough FVIII activity close to 10% at steady state. Five patients developed anti-N8-GP binding antibodies after 42 to 91 exposure days, one of whom developed an inhibitor to FVIII. Anti-N8-GP antibody appearance was associated with a decline in FVIII plasma activity in four of the five patients. Five patients reported a total of nine treatment-requiring bleeding episodes during prophylaxis.

Conclusions: Subcutaneous administration of N8-GP is associated with a high incidence of antibodies in PTPs with severe hemophilia A. Further clinical development of s.c. N8-GP has been suspended.

Keywords: antibodies; factor VIII; hemophilia A; subcutaneous infusions.

Conflict of interest statement

Robert Klamroth received research support, consulting fees, and honoraria from Bayer, Biomarin, Biotest, Catalyst, CSL Behring, Novo Nordisk, Octapharma, Pfizer, Sanofi, Sobi, and Takeda. Clemens Feistritzer received research support from Sobi and Biotest; speaker fees from Bayer, Novo Nordisk, Roche, Shire/Takeda, and Sobi; and consultancy from Baxalta/Shire, Bayer, Kymab, Novo Nordisk, Roche, and Sobi. Steven R. Lentz has received grant support and personal fees from Novo Nordisk and has served as a paid consultant for Novo Nordisk. Ute Friedrich, Kirsten Reichwald, and Marek Zak are employees of Novo Nordisk. Pratima Chowdary has served on advisory boards for Bayer, Baxalta/Shire, Biogen Idec, CSL Behring, Chugai, Freeline, Novo Nordisk, Pfizer, Roche, Sanofi, and Sobi; and has received research funding from Bayer, CSL Behring, Novo Nordisk, Pfizer, and Sobi. This research was funded by Novo Nordisk.

© 2019 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals, Inc. on behalf of International Society on Thrombosis and Haemostasis.

Figures

Figure 1

Alleviate 1 trial design and patient flow. In part A, 27 patients were screened and 24 started treatment. In part B, 26 patients were included and started on trial product. Of these, a total of 14 patients continued from part A to part B and 12 additional patients were included. PK assessments were performed during Visits 2‐4 in part A and at Visits 2‐10 in part B. Clear boxes indicate screening visits, black boxes indicate dosing visits, and gray boxes indicate follow‐up visits. D, day; PK, pharmacokinetics; SAE, serious adverse event; V, visit; W, week

Figure 2

PK assays were performed using a chromogenic assay with a product‐specific standard. Data represent geometric mean (CV%) FVIII activity and are plotted on a log scale. Part A: mean pharmacokinetic profiles of FVIII activity after four different single doses of s.c. N8‐GP. Values below LLOQ (0.9 IU/dL) were predicted using population‐based approach. Part B: mean pre‐dose FVIII activity at Visit 2 (first dose in part B), Visit 3 (after 7 days of daily doses), Visit 4, Visit 5, Visit 6, Visit 7, and Visit 8. Patients received a fixed dose of s.c. N8‐GP at 4000 IU/day (except for one patient who received 2000 IU/day). Error bars are standard error of the mean. Geometric mean (CV%) = 11.5 (64.6) IU/dL. min; max = 3.4; 45.4. CV, coefficient of variation; FVIII, factor VIII; LLOQ, lower limit of quantification; PK, pharmacokinetics; s.c. subcutaneous

Figure 3

Binding antibody response of patients who developed anti‐N8‐GP antibodies in part B. Binding antibody response was calculated as percentage bound antibody over total. Response was measured at each clinic visit. Anti‐N8‐GP antibodies were detected between 42 and 91 s.c. N8‐GP exposure days. The dashed line represents patient A, who developed FVIII inhibitors, had high levels of binding antibodies, N8‐GP‐specific IgG4, and affected FVIII trough levels. The black lines represent patients B‐D, who had high levels of binding antibodies and also had N8‐GP‐specific IgG4 detected, as well as affected FVIII trough levels. The gray line represents patient E who had low levels of binding antibodies detected, with no IgG4 detected and no effect on FVIII activity levels. FVIII, factor VIII; V, visit

Figure 4

FVIII activity pre‐dose versus time. Pre‐dose FVIII activity measurements in individual patients without (A; n = 21) and with anti‐N8‐GP binding antibodies (B; n = 5) during part B. The pre‐dose FVIII activity in patients with binding antibodies declined markedly over the course of the trial (B), which was not the case for patients who did not develop anti‐N8‐GP binding antibodies (A). FVIII, factor VIII