A randomized, adaptive design, double-blind, 3-arm, parallel study assessing the pharmacokinetics and safety of AVT02, a high-concentration (100 mg/mL) Adalimumab biosimilar, in healthy adult subjects (ALVOPAD FIRST)

ABSTRACT

Background

This study (ALVOPAD FIRST) assessed bioequivalence, safety, and immunogenicity of AVT02, an adalimumab biosimilar, compared with reference product adalimumab (EU- and US-approved Humira®).

Methods

Healthy subjects (N = 392) were randomized 1:1:1 to receive one 40 mg dose of AVT02, EU-reference product, or US-reference product subcutaneously. An interim analysis was planned when ~30 subjects per arm had completed the study, to optimize final sample size. The primary PK parameters were C_max, AUC_0-t, and AUC_0-inf. Bioequivalence was demonstrated if the 90% confidence intervals (CI) for the ratio of geometric means for the primary pharmacokinetic (PK) parameters were all contained within the prespecified margins of 80% and 125%. Safety and immunogenicity were assessed until Day 64.

Results

The 90% CI for the ratio of geometric means for the primary PK parameters, based on Fisher’s Combination test analysis, were all contained within the prespecified bioequivalence margins of 80% and 125%, supporting the demonstration of bioequivalence between AVT02 and both EU- and US-reference product. The safety and immunogenicity profiles were comparable across all three treatment arms.

Conclusion

PK bioequivalence was supported between AVT02, US-licensed- and EU-approved-reference product adalimumab. Similar safety and immunogenicity were also demonstrated.

Trial Registration

The trial is registered at ClinicalTrials.gov (CT.gov identifier: NCT03849313).

KEYWORDS:

• Adalimumab
• adaptive design
• AVT02
• bioequivalence
• biosimilar
• pharmacokinetics

Acknowledgments

The authors thank the subjects who participated in the study and all the investigators who contributed. The authors additionally thank Joseph McClellan of Alvotech for strategic guidance, and Lorna Rettig of Alvotech for medical writing assistance.

Supplemental data

Supplemental data for this article can be accessed here.

Author contributions

Christopher Wynne, Heimo Stroissnig. Joanna Sobierska, Eris Guenzi, Hendrik Otto, Abid Sattar, Halimu N. Haliduola, Richard Kay, and Fausto Berti were involved in the conception and design of the study. Christian Schwabe, Charlotte Lemech, Joanna Sobierska and Roshan Dias were involved in the provision of study materials and patients and acquisition of the data. Christopher Wynne, Heimo Stroissnig, Joanna Sobierska, Hendrik Otto, Abid Sattar, Halimu N. Haliduola, and Fausto Berti did the analysis and/or the interpretation of the data. All authors revised the report critically. All authors approved the final version.

Declaration of Interests

Christopher Wynne and Christian Schwabe are employees of, and hold shares in, New Zealand Clinical Research that received payment for carrying out the study. Charlotte Lemech is an employee of Scientia Clinical Research that received payment for carrying out the study. Heimo Stroissnig, Roshan Dias, Joanna Sobierska, Eric Guenzi, Hendrik Otto, Abid Sattar, Halimu N. Haliduola, and Fausto Berti are employees at Alvotech. Richard Kay’s company has received consultancy fees in relation to this study and in other studies conducted by Alvotech, but no consultancy fees have been received in relation to the writing of this manuscript.

Reviewer disclosures

One referee is an employee of Mount Sinai and receives research funds from: Abbvie, Amgen, Arcutis, Avotres, Boehringer Ingelheim, Dermavant Sciences, Eli Lilly, Incyte, Janssen Research & Development, LLC, Ortho Dermatologics, Regeneron, and UCB, Inc., and is a consultant for Aditum Bio, Almirall, AltruBio Inc., AnaptysBio, Arcutis, Inc., Aristea Therapeutics, Arrive Technologies, Avotres Therapeutics, BiomX, Boehringer-Ingelheim, Bristol-Myers Squibb, Cara Therapeutics, Castle Biosciences, Corrona, Dermavant Sciences, Dr. Reddy’s Laboratories, Evelo Biosciences, Evommune, Inc., Facilitatation of International Dermatology Education, Forte Biosciences, Foundation for Research and Education in Dermatology, Helsinn Therapeutics, Hexima Ltd., LEO Pharma, Meiji Seika Pharma, Mindera, Pfizer, Seanergy, and Verrica. One reviewer receives research grants from Pfizer, AbbVie, and BMS. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Additional information

Funding

This study was funded by Alvotech.