Alizé Pharma 3 : IGFBP-2 peptides in rare diseases

Company   Alize Pharma 3
Program   IGFBP-2 peptides in rare metabolic and musculoskeletal diseases
Stage of development   Lead optimization
Status   Unpartnered
Investors  

Sofimac Partners (Emergence Innovation 1)

initiative Octalfa

Sham Innovation Santé

RhônesAlpes Création

Crédit Agricole Création

TAB Consulting

 

 

AZP3404, an IGFBP-2 derived peptide analog for the treatment of metabolic & musculoskeletal rare diseases

 

Insulin-like Growth Factor Binding Protein-2 (IGFBP-2), a leptin regulated gene, has been shown to improve glucose control and insulin sensitivity in leptin and insulin resistant conditions, independently from its IGF-binding properties. In addition, IGFBP-2 modulates fat and bone metabolism by stimulating osteoblasts and inhibiting adipocyte differentiation.

 

Alizé Pharma 3 and its academic partners at University of North Carolina at Chapel Hill and University of Maine have identified and optimized short peptide fragments of IGFBP-2 that exhibit its metabolic and bone biological activities without binding to IGFs. 

 

AZP-3404 is a stabilized analog of one of these IGFBP-2 fragments. AZP-3404 has improved pharmacokinetic profile, is highly potent on glucose control in animal models with severe insulin resistance and restores trabecular bone formation and decreases fat deposition in animal models of bone deficiency.

 

Based on its pharmacological profile, AZP-3404 is intended to be developed in rare metabolic diseases associated with insulin resistance and/or leptin resistance. These include syndromes of extreme insulin resistance, LepR and MC4R deficiencies, as well as several ciliopathies and lipodystrophy syndromes. 

 

AZP-3404 and other IGFBP-2-derived peptides also have the potential to address unmet medical needs in rare musculoskeletal indications such as Osteogenesis Imperfecta.

 

References

Metabolism

  • Wheatcroft SB et al. IGF-binding protein 2 protects against the development of obesity and insulin resistance. Diabetes 56:285-294, 2007
  • Hedbacker K et al. Antidiabetic effects of IGFBP2, a leptin-regulated gene. Cell Metabolism, 11:11-22, 2010
  • Xi G et al. The heparin-binding domains of IGFBP-2 mediate its inhibitory effect on preadipocyte differentiation and fat development in male mice. Endocrinology, 154:4146-4157, 2013
  • Yau SW et al. IGFBP-2 enhances insulin signaling pathways in human skeletal muscle by cell surface binding – an IGF independent process? Endocrine Society 96th Annual Meeting, Chicago, SAT-1072, 2014
  • Yau SW et al. IGFBP-2 inhibits adipogenesis and lipogenesis in human visceral, but not subcutaneous, adipocytes. Int J of Obesity, 39: 770-781, 2015
  • Assefa B et al. Insulin-like growth factor (IGF) binding protein-2, independently of IGF-1, induces GLT-4 translocation and glucose uptake in 3T3-L1 adipocytes

Bone

  • DeMambro VE et al. Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice. Endocrinology. 149(5):2051-61 (2008)
  • Kawai M et al. The heparin-binding domain of IGFBP-2 has insulin-like growth factor binding-independent biologic activity in the growing skeleton. J Biol Chem. 22;286(16):14670-80 (2011)
  • Xi G et al. IGFBP-2 Directly Stimulates Osteoblast Differentiation. J Bone Miner Res. 29(11):2427-38 (2014)
  • Shen X etal. The Coordinate Cellular Response to Insulin-like Growth Factor-I (IGF-I) and Insulin-like Growth Factor-binding Protein-2 (IGFBP-2) Is Regulated through Vimentin Binding to Receptor Tyrosine Phosphatase β (RPTPβ). J Biol Chem. 1;290(18):11578-90 (2015)
  • Xi G et al. IRS-1 Functions as a Molecular Scaffold to Coordinate IGF-I/IGFBP-2 Signaling During Osteoblast Differentiation. J Bone Miner Res. (2016)
  • Xi G et al. A unique peptide containing the heparin binding domain of IGFBP-2 increases bone mass in OVX rats. ASBMR (2016)