title: Does Activin Receptor Blockade by Bimagrumab (BYM338) Pose Detrimental Effects on Bone Healing in a Rat Fibula Osteotomy Model?
abstract: Bimagrumab (BYM338) is a novel fully human monoclonal antibody that exerts strong promyogenic effects on skeletal muscle by blocking activin type II receptors (ActRII). We investigated whether such blockade of ActRII by bimagrumab manifests any detrimental effect on outcomes of bone healing in a rat fibula osteotomy model. Animals (n = 150) were divided into 11 groups and received weekly treatment with either bimagrumab (10 or 100 mg/kg) or vehicle. Progression and outcomes of bone healing were assessed by lateral radiographs in vivo as well as by peripheral quantitative computed tomography (pQCT), 4-point bending test, and microscopic examination of the excised fibula at Day 29 or later. The radiographic progression of bone healing showed no significant differences between treatment groups in any comparative setting. In 3-month-old animals, pQCT revealed slightly reduced immature callus size and bone mineral content in bimagrumab-treated animals compared with vehicle-treated animals at Day 29 (p < 0.05). There were, however, no differences in mature callus size, bone mineral density, or biomechanical competency. The aforementioned effects on immature callus size were not present when the treatment was initiated 4 weeks post osteotomy or when treating 6-month-old animals. In summary, these findings suggest that there is no major impact of ActRII blockade on overall fracture healing, and delayed treatment initiation can bypass the small and transient effect of the therapy on immature callus formation observed in younger animals. Verification of these findings in humans is the subject of an ongoing clinical trial on elderly hip fracture patients.
authors.affiliation: Novartis Pharma AG, Fabrikstrasse 12-3.03.23, Postfach, 4002, Basel, Switzerland. laszlo.tanko@novartis.com.
authors.forename: László B
authors.initials: LB
authors.lastname: Tankó
authors.affiliation: Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Jörg
authors.initials: J
authors.lastname: Goldhahn
authors.affiliation: Musculoskeletal Research, Charles River, Montreal, Canada.
authors.forename: Aurore
authors.initials: A
authors.lastname: Varela
authors.affiliation: Musculoskeletal Research, Charles River, Montreal, Canada.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Lesage
authors.affiliation: Musculoskeletal Research, Charles River, Montreal, Canada.
authors.forename: Susan Y
authors.initials: SY
authors.lastname: Smith
authors.affiliation: Novartis Institute for Biomedical Research, Basel, Switzerland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Pilling
authors.affiliation: Novartis Institute for Biomedical Research, Basel, Switzerland.|ADC Therapeutics, London, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Chivers
mesh_terms: D029404:Activin Receptors / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D001696:Biomechanical Phenomena / Q000187:drug effects; D015519:Bone Density / Q000187:drug effects*; D002146:Bony Callus / Q000187:drug effects; D005360:Fibula / Q000187:drug effects*; D017102:Fracture Healing / Q000187:drug effects; D050723:Fractures, Bone / Q000188:drug therapy*; D008297:Male; D010027:Osteotomy / Q000379:methods; D017207:Rats, Sprague-Dawley
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D029404:Activin Receptors; C000596367:bimagrumab
keywords: 4-Point bending test; Activin type II receptors; Callus formation; Fibular osteotomy; Imaging