Bioequivalence of a Liquid Formulation of Alpha₁-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha₁-PI) in Alpha₁-Antitrypsin Deficiency

ABSTRACT

This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma–derived alpha₁-proteinase inhibitor, Liquid Alpha₁-PI, compared with the Lyophilized Alpha₁-PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha₁-antitrypsin deficiency (AATD). In this double-blind, randomized, 20-week crossover study, 32 subjects with AATD were randomized to receive 8 weekly infusions of 60 mg/kg of Liquid Alpha₁-PI or Lyophilized Alpha₁-PI. Serial blood samples were drawn for 7 days after the last dose followed by 8 weeks of the alternative treatment. The primary endpoint was bioequivalence at steady state, as measured by area under the concentration versus time curve from 0 to 7 days (AUC_0–7 days) postdose using an antigenic content assay. Bioequivalence was defined as 90% confidence interval (CI) for the ratio of the geometric least squares (LS) mean of AUC_0–7 days for both products within the limits of 0.80 and 1.25. Safety and immunogenicity were assessed. Mean alpha₁-PI concentration versus time curves for both formulations were superimposable. Mean AUC_0–7 days was 20 320 versus 19 838 mg × h/dl for Liquid Alpha₁-PI and Lyophilized Alpha₁-PI, respectively. The LS mean ratio of AUC_0–7 days (90% CI) for Liquid Alpha₁-PI versus Lyophilized Alpha₁-PI was 1.05 (1.03–1.08), indicating bioequivalence. Liquid Alpha₁-PI was well tolerated and adverse events were consistent with Lyophilized Alpha₁-PI. Immunogenicity to either product was not detected. In conclusion, Liquid Alpha₁-PI is bioequivalent to Lyophilized Alpha₁-PI, with a similar safety profile. The liquid formulation would eliminate the need for reconstitution and shorten preparation time for patients receiving augmentation therapy for AATD.

KEYWORDS:

• Antigenic content assay
• augmentation therapy
• clinical trial
• functional activity assay
• pharmacokinetics

Declaration of Interest

AF Barker: Clinical research funding provided by Grifols Therapeutics Inc.

MA Campos: Research grants from the Alpha-1 Foundation and CSL Behring; participated in clinical trials sponsored by Baxalta, CSL Behring, and Grifols Therapeutics Inc.; participated in advisory boards for CSL Behring and Grifols Therapeutics Inc.

ML Brantly: Research grants from Grifols Therapeutics Inc.; owner of GeneAidyx.

JM Stocks: Research grants from Grifols Therapeutics Inc. and Kamada.

RA Sandhaus: Research grants from CSL Behring and Grifols Therapeutics Inc.; trains speakers on their speaker bureau for Grifols Therapeutics Inc.; advisory boards for Shire (Baxalta).

D Lee: Speaker for Boehringer Ingleheim, Genentech, Grifols Therapeutics Inc., and Otsuka; participated in clinical trials sponsored by Grifols Therapeutics Inc.

K Steinmann, J Lin and S Sorrells: employees and stockholders of Grifols Therapeutics Inc.

Acknowledgments

The authors would like to thank the study coordinators for their dedication and care of the study participants, and the participants of this study for giving of their valuable time. Writing and editorial assistance was provided to the authors by David Macari, PhD, and Susan Sutch, PharmD, CMPP, on behalf of Evidence Scientific Solutions, Philadelphia, Pennsylvania, USA, and funded by Grifols Inc., Research Triangle Park, North Carolina, USA.

Funding

Grifols Therapeutics Inc. (Research Triangle Park, NC, USA) funded this study.

Authors' Contributions

AFB, MAC, MLB, JMS, RAS, DL, KS, JL, and SS contributed to the study design and implementation and provided meaningful input to this manuscript. JL provided statistical analyses for this study.