Development of a First-in-Class Unimolecular Dual GIP/GLP-2 Analogue, GL-0001, for the Treatment of Bone Fragility

Abstract

Due to ageing of the population, bone frailty is dramatically increasing worldwide. Although some therapeutic options exist, they do not fully protect or prevent against the occurrence of new fractures. All current drugs approved for the treatment of bone fragility target bone mass. However, bone resistance to fracture is not solely due to bone mass but relies also on bone ECM material properties, i.e. the quality of the bone matrix component. Here, we introduce the first-in-class unimolecular dual GIP/GLP-2 analogues, GL-0001, that activate simultaneously the glucose-dependent insulinotropic polypeptide receptor (GIPr) and the glucagonlike peptide-2 receptor (GLP-2r). GL-0001 acts synergistically through a cAMP-LOX pathway to enhance collagen maturity. Furthermore, in mice with ovariectomy-induced bone fragility, GL-0001 prevented excess trabecular bone degradation at the appendicular skeleton and also enhanced bone ECM material properties through reduction of the degree of mineralization and augmentation in enzymatic collagen crosslinking. These results demonstrate that targeting bone ECM material properties is a viable option to enhance bone strength and opens an innovative pathway for the treatment of patients suffering of bone fragility.

Gut-Derived Peptide Hormone Analogues and Potential Treatment of Bone Disorders in Obesity and Diabetes Mellitus

“…Given recent approval of tirzepatide for T2DM, 61 , 118 alongside current clinical evaluation of other similar dual- and triple-acting entities, 120 it seems clear that the same rationale could be applied to bone-targeting unimolecular peptides. Consequently, the powerful, and likely complementary effects of GIP and GLP-2 on bone turnover, 89 , 126 support this paradigm. Thus, GL-0001, a first in class GIP/GLP-2 dual-acting analogue, positively modified biomechanical parameters of bone in mice by increasing fracture resistance, preventing trabecular bone degradation and augmenting collagen cross-linking 126 ( Table 1 ).…”

“…Consequently, the powerful, and likely complementary effects of GIP and GLP-2 on bone turnover, 89 , 126 support this paradigm. Thus, GL-0001, a first in class GIP/GLP-2 dual-acting analogue, positively modified biomechanical parameters of bone in mice by increasing fracture resistance, preventing trabecular bone degradation and augmenting collagen cross-linking 126 ( Table 1 ). Moreover, GIP-GLP-2 receptor co-agonists for use in the human setting have also recently been described, that reassuringly were shown to possess similar efficacy at the level of the bone as combined treatment with respective parent peptides, 89 suggesting translation of benefits to the clinic is conceivable.…”

Effect of incretins on skeletal health

“…A unimolecular GIP/GLP-2 receptor analogue has been introduced and used in ovariectomized mice. Based on three-point bending of the right femurs, the GIP/GLP-2 receptor analogue improved biomechanical structures compared to zoledronic acid which was used as a positive comparator [29 ▪▪ ].…”

Microbiome-induced Increases and Decreases in Bone Tissue Strength can be Initiated After Skeletal Maturity

“…Hence, new methods to address bone fragility are essential to advancing fracture prevention beyond current capabilities. The mechanical properties of bone tissue (the mineralized matrix) contribute to bone strength but are not directly addressed by existing therapeutics, although recent discoveries suggest the possibility of agents that enhance bone matrix (2) . Here we examine the gut microbiome's effect on the strength of bone matrix.…”