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Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338)

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Abstract

Background

Bimagrumab is a human monoclonal antibody binding to the activin type II receptor with therapeutic potential in conditions of muscle wasting and obesity. This phase I study evaluated the pharmacokinetics (PK), pharmacodynamics (PD), and safety of various dose regimens of bimagrumab and routes of administration in healthy older adults.

Methods

This was a randomized, double-blind, placebo-controlled, parallel-arm, multiple-dose study in older adult men and women (aged ≥ 70 years, body mass index [BMI] 18–34 kg/m2) with stable health and diet. The study comprised seven treatment groups (Cohorts 1–7). Participants received bimagrumab or placebo treatment every 4 weeks for three doses (Cohorts 1 [700 mg] and 2 [210 mg] intravenous infusion; Cohorts 3 [1500 mg] and 4 [525 mg] subcutaneous infusion), or every week for 12 doses (Cohorts 5 [300 mg], 6 [150 mg], and 7 [52.5 mg] subcutaneous bolus injection) and were followed up until week 20. Blood samples were collected for bimagrumab PK analysis. PD were assessed by dual energy X-ray absorptiometry to quantify the change from baseline in lean body mass (LBM) and fat body mass (FBM) compared with placebo. Safety was assessed throughout the study.

Results

Eighty-four of 91 (92.3%) randomized participants (mean age 74.5 years; BMI 28.0 kg/m2) completed the study. Demographic characteristics were generally balanced across the groups. A target-mediated drug disposition profile was observed following both intravenous and subcutaneous administration. The absolute subcutaneous bioavailability was estimated at approximately 40%. LBM increased by 4–6% (1.5–2 kg) from baseline throughout the treatment period for intravenous and subcutaneous regimens, except for the 52.5 mg subcutaneous dose, which did not differ from placebo. Concurrently, there was a decrease in FBM (approximately 2–3 kg) for all intravenous and subcutaneous regimens. Bimagrumab was generally safe and well tolerated; adverse events were mostly mild to moderate in severity.

Conclusions

Dose levels of bimagrumab administered weekly subcutaneously resulted in PK profiles and PD effects comparable with monthly intravenous dosing, which supports the feasibility of the subcutaneous route of administration for bimagrumab for future clinical development.

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Acknowledgements

The authors thank Hans-Joachim Wallny (Project Technical Leader) and Nicole Getzmann (Clinical Trial Leader; assisted in design and execution of the study). The authors acknowledge BioTel Research, Rochester, NY, USA, for medical imaging support. The authors also thank Hardik Ashar and Rohita Sri Gattoju for providing medical writing support, and Jitendriya Mishra for internal review support for the manuscript, employees of Novartis Healthcare in Hyderabad, India, in accordance with Good Publication Practice guidelines.

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Authors and Affiliations

  1. Translational Medicine, Novartis Institutes for BioMedical Research, WSJ-386/10/48.50, 4002, Basel, Switzerland

    Olivier Petricoul, Arman Nazarian, Ursula Schramm, Didier Laurent & Ronenn Roubenoff

  2. Novartis Pharma AG, Basel, Switzerland

    Uwe Schuehly & Olivier J. David

  3. Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA

    Jens Praestgaard & Dimitris A. Papanicolaou

  4. Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, MA, USA

    Daniel Rooks

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  1. Olivier Petricoul
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Corresponding author

Correspondence to Olivier Petricoul.

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Author contributions

All authors participated in the study design and implementation and/or conduct of the study. All authors read and approved the final manuscript.

Funding

This study was funded by Novartis Institutes for BioMedical Research, Basel, Switzerland

Conflict of interest

Olivier Petricoul, Arman Nazarian, Uwe Schuehly, Ursula Schramm, Olivier J. David, Didier Laurent, Jens Praestgaard, Ronenn Roubenoff, Dimitris A. Papanicolaou, and Daniel Rooks are employees of Novartis and, as such, may be eligible for Novartis stock and stock options.

Data availability

Data that support the findings of this study may be available upon reasonable request. Inquiries should be sent to info@versanisbio.com

Role of the sponsor

The study was designed by the Novartis Institutes of BioMedical Research (NIBR) and executed in collaboration with external principal investigators and their study sites. The data were analyzed by an independent contractor, and the NIBR study team was responsible for data interpretation.

Ethics approval

The study was conducted according to the ethical principles of the Declaration of Helsinki. The study protocol was reviewed by the Institutional Review Board for each center.

Consent to participate

Written informed consent was obtained from each participant before conducting any study-specific procedures.

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Not applicable.

Code availability

Not applicable.

Supplementary Information

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Supplementary file1 (DOCX 273 KB)

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Petricoul, O., Nazarian, A., Schuehly, U. et al. Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338). Clin Pharmacokinet 62, 141–155 (2023). https://doi.org/10.1007/s40262-022-01189-0

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  • DOI: https://doi.org/10.1007/s40262-022-01189-0

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