A single-dose euglycaemic clamp study in two cohorts to compare the exposure of SAR341402 (insulin aspart) Mix 70/30 with US- and European-approved versions of insulin aspart Mix 70/30 and SAR341402 rapid-acting solution in subjects with type 1 diabetes

Christoph Kapitza, Leszek Nosek, Wolfgang Schmider, Lenore Teichert, Bhaswati Mukherjee, Irene Nowotny, Christoph Kapitza, Leszek Nosek, Wolfgang Schmider, Lenore Teichert, Bhaswati Mukherjee, Irene Nowotny

Abstract

Aim: To compare the pharmacokinetic exposure of SAR341402 Mix 70/30 (SARAsp -Mix) with US- and European (EU)-approved versions of insulin aspart Mix 70/30 (NovoLog Mix 70/30 [NN-Mix-US]/NovoMix 30 [NN-Mix-EU]) and SAR341402 insulin aspart solution (SAR-Asp) in subjects with type 1 diabetes.

Materials and methods: This was a randomized, double-blind, crossover trial in two cohorts. Fifty-two subjects received a single subcutaneous 0.3 U/kg dose of each treatment and underwent a euglycaemic clamp procedure lasting for a maximum of 24 hours after dosing. In cohort 1, subjects (N = 36) were exposed once each to SARAsp -Mix, NN-Mix-US and NN-Mix-EU. In cohort 2, subjects (N = 16) were exposed once each to SARAsp -Mix and SAR-Asp.

Results: Of the 52 subjects randomized, 48 completed all treatment periods. In cohort 1, the extent of exposure (total and maximum concentration) was similar among the three treatments, with the 90% confidence intervals for pairwise treatment ratios meeting the predefined acceptance range (0.80 to 1.25). In cohort 2, statistically significant differences (P < .001) in early (0-4 hours) and intermediate (4-12 hours) exposure to SARAsp -Mix compared with SAR-Asp were observed, all exceeding a 20% difference. Pharmacodynamic results were in support of the pharmacokinetic findings for both cohorts. All treatments were well tolerated and there were no relevant differences in safety variables among treatments.

Conclusions: SARAsp -Mix showed similar pharmacokinetic exposure to commercially available insulin aspart Mix 70/30 formulations, and a distinct exposure profile compared with SAR-Asp.

Keywords: biosimilar, insulin aspart mix, pharmacodynamics, pharmacokinetics, phase I study, premix, type 1 diabetes.

Conflict of interest statement

C.K. is an employee and co‐owner of Profil, which has received research funds from Adocia, Biocon, Boehringer Ingelheim Pharmaceuticals, Dance Biopharm, Eli Lilly and Company, Gan & Lee Pharmaceuticals, MedImmune, Mylan, Nordic Bioscience, Nestlé, Novo Nordisk, Poxel SA, Sanofi‐Aventis, Wockhardt, Xeris Pharmaceuticals and Zealand Pharma. L.N. is an employee of Profil. W.S., L.T. and B.M. are employees of Sanofi. I.N. is a former employee of Sanofi and is a current consultant to Sanofi.

© 2020 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
Pharmacokinetic profiles for SARAsp‐Mix, NN‐Mix‐US, NN‐Mix‐EU and SAR‐Asp versus time. Mean insulin aspart plasma concentrations in (A) cohort 1 and (B) cohort 2. The horizontal dotted line represents the lower limit of quantification (100 pg/mL)

References

    1. European Medicines Agency . Insulin aspart Sanofi. Summary of product characteristics, 2020. https://. Accessed July 22, 2020.
    1. European Medicines Agency . NovoRapid. Summary of product characteristics, 2019. . Accessed July 22, 2020.
    1. Novo Nordisk . NovoLog, insulin aspart injection 100 units/mL, NovoNordisk, 2019. . Accessed July 22, 2020.
    1. Novo Nordisk . NovoLog Mix 70/30 insulin aspart protamine and insulin aspart injectable suspesion 100 units/mL, NovoNordisk, 2019. . Accessed July 22, 2020.
    1. European Medicines Agency . NovoMix 30 (30% insulin aspart and 70% insulin aspart protamine). Summary of product characteristics, updated August 16, 2019. https://. Accessed July 22, 2020.
    1. European Medicines Agency . Guideline on non‐clinical and clinical development of similar biological medicinal products containing recombinant human insulin and insulin analogues, February 26, 2015. . Accessed July 22, 2020.
    1. US Food and Drug Administration Center for Drug Evaluation and Research (CDER) . Guidance for industry. Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention. February 2008:1–30. . Accessed July 22, 2020.
    1. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER) . Guidance for Industry: Questions and Answers on Biosimilar Development and the BPCI Act (Revision 1), December 2018:1–19. . Accessed July 22, 2020.
    1. US Food and Drug Administration, Center for Drug Evaluation and Research (CDER) . Guidance for Industry. New and Revised Draft Q&As on Biosimilar Development and the BPCI Act (Revision 2) (Draft Guidance), December 2018:1–14. . Accessed July 22, 2020.
    1. Kapitza C, Nosek L, Schmider W, Teichert L, Nowotny I. Single‐dose euglycemic clamp study demonstrating pharmacokinetic and pharmacodynamic similarity between SAR341402 insulin aspart and US‐ and EU‐approved versions of insulin aspart in subjects with type 1 diabetes. Diabetes Technol Ther. 2020;22:278‐284.
    1. . A randomized, double‐blind, single‐dose, 2‐treatment, 2‐period, 2‐sequence crossover study to compare exposure and activity of SAR341402 to NovoRapid using the euglycemic clamp technique, in healthy Japanese male subjects. JapicCTI‐No. JapicCTI‐205379. . Accessed July 22, 2020.
    1. Garg SK, Wernicke‐Panten K, Wardecki M, et al. Efficacy and safety of insulin aspart biosimilar SAR341402 versus originator insulin aspart in people with diabetes treated for 26 weeks with multiple daily injections in combination with insulin glargine: a randomized open‐label trial (GEMELLI 1). Diabetes Technol Ther. 2020;22:85‐95.
    1. Garg SK, Wernicke‐Panten K, Wardecki M, et al. Safety, immunogenicity, and glycemic control of insulin aspart biosimilar SAR341402 versus originator insulin aspart in people with diabetes also using insulin glargine: 12‐month results from the GEMELLI 1 trial. Diabetes Technol Ther. 2020;22:516‐526.
    1. Thrasher J, Polsky S, Hovsepian L, et al. Safety and tolerability of insulin aspart biosimilar SAR341402 versus originator insulin aspart (novolog) when used in insulin pumps in adults with type 1 diabetes: a randomized, open‐label clinical trial. Diabetes Technol Ther. 2020;22:666‐673.
    1. Liebl A, Prusty V, Valensi P, Yang W, Strojek K, Linjawi S. Ten years of experience with biphasic insulin aspart 30: from drug development to the latest clinical findings. Drugs. 2012;72:1495‐1520.
    1. Liebl A, Mohan V, Yang W, Strojek K, Linjawi S. 15 years of experience with biphasic insulin aspart 30 in type 2 diabetes. Drugs R D. 2018;18:27‐39.
    1. American Diabetes Association: 9 . Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes‐2020. Diabetes Care. 2020;43(suppl 1):S98‐S110.
    1. Davies MJ, D'Alessio DA, Fradkin J, et al. Management of hyperglycemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetes Care. 2018;41:2669‐2701.
    1. Anyanwagu U, Mamza J, Gordon J, Donnelly R, Idris I. Premixed vs basal‐bolus insulin regimen in type 2 diabetes: comparison of clinical outcomes from randomized controlled trials and real‐world data. Diabet Med. 2017;34:1728‐1736.
    1. Jia W, Xiao X, Ji Q, et al. Comparison of thrice‐daily premixed insulin (insulin lispro premix) with basal‐bolus (insulin glargine once‐daily plus thrice‐daily prandial insulin lispro) therapy in east Asian patients with type 2 diabetes insufficiently controlled with twice‐daily premixed insulin: an open‐label, randomised, controlled trial. Lancet Diabetes Endocrinol. 2015;3:254‐262.
    1. Ray KK, Kendall DM, Zhao Z, et al. A multinational observational study assessing insulin use: understanding the determinants associated with progression of therapy. Diabetes Obes Metab. 2019;21:1101‐1110.
    1. Giugliano D, Chiodini P, Maiorino MI, Bellastella G, Esposito K. Intensification of insulin therapy with basal‐bolus or premixed insulin regimens in type 2 diabetes: a systematic review and meta‐analysis of randomized controlled trials. Endocrine. 2016;51:417‐428.
    1. Kalra S, Czupryniak L, Kilov G, et al. Expert opinion: patient selection for premixed insulin formulations in diabetes care. Diabetes Ther. 2018;9:2185‐2199.
    1. Rizvi AA. Treatment of type 2 diabetes with biphasic insulin analogues. Eur Med J Diabetes. 2016;4:74‐83.
    1. Kumar A, Awata T, Bain SC, et al. Clinical use of the co‐formulation of insulin degludec and insulin aspart. Int J Clin Pract. 2016;70:657‐667.
    1. Fralick M, Kesselheim AS. The U.S. insulin crisis — rationing a lifesaving medication discovered in the 1920s. New Engl J Med. 2019;381:1793‐1795.
    1. EU Clinical Trials Register . A 26‐week, randomized, open‐label, parallel‐group comparison of SAR341402 Mix 70/30 to NovoMix®30 in adult patients with diabetes mellitus using pre‐mix insulin analogs. EudraCT Number: 2017‐000092‐84. https://. Accessed July 22, 2020.
    1. Heise T, Zijlstra E, Nosek L, Heckermann S, Plum‐Mörschel L, Forst T. Euglycaemic glucose clamp: what it can and cannot do, and how to do it. Diabetes Obes Metab. 2016;18:962‐972.
    1. Swinnen SG, Holleman F, DeVries JH. The interpretation of glucose clamp studies of long‐acting insulin analogues: from physiology to marketing and back. Diabetologia. 2008;51:1790‐1795.

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren