Petricoul, Olivier, Nazarian, Arman, Schuehly, Uwe, Schramm-Franz, Ursula, David, Olivier, Laurent, Didier, Praestgaard, Jens, Roubenoff, Ronenn, Papanicolaou, Dimitris and Rooks, Daniel (2022) Pharmacokinetics and Pharmacodynamics of Bimagrumab (BYM338). Clinical pharmacokinetics, 62 (1). pp. 141-155. ISSN 1179-1926

Abstract

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.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.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.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.

Item Type:	Article
Keywords:	Male Humans Female Aged Antibodies, Monoclonal, Humanized Antibodies, Monoclonal Administration, Intravenous Injections, Subcutaneous Double-Blind Method
Date Deposited:	10 Mar 2023 00:45
Last Modified:	10 Mar 2023 00:45
URI:	https://oak.novartis.com/id/eprint/47560