A multi-model approach to predict efficacious clinical dose for an anti-TGF-β antibody (GC2008) in the treatment of osteogenesis imperfecta

Abstract

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited bone dysplasias characterized by reduced skeletal mass and bone fragility. Although the primary manifestation of the disease involves the skeleton, OI is a generalized connective tissue disorder that requires a multidisciplinary treatment approach. Recent studies indicate that application of a transforming growth factor beta (TGF-β) neutralizing antibody increased bone volume fraction (BVF) and strength in an OI mouse model and improved bone mineral density (BMD) in a small cohort of patients with OI. In this work, we have developed a multitiered quantitative pharmacology approach to predict human efficacious dose of a new anti-TGF-β antibody drug candidate (GC2008). This method aims to translate GC2008 pharmacokinetic/pharmacodynamic (PK/PD) relationship in patients, using a number of appropriate mathematical models and available preclinical and clinical data. Compartmental PK linked with an indirect PD effect model was used to characterize both pre-clinical and clinical PK/PD data and predict a GC2008 dose that would significantly increase BMD or BVF in patients with OI. Furthermore, a physiologically-based pharmacokinetic model incorporating GC2008 and the body's physiological properties was developed and used to predict a GC2008 dose that would decrease the TGF-β level in bone to that of healthy individuals. By using multiple models, we aim to reveal information for different aspects of OI disease that will ultimately lead to a more informed dose projection of GC2008 in humans. The different modeling efforts predicted a similar range of pharmacologically relevant doses in patients with OI providing an informed approach for an early clinical dose setting.

FIGURE 1

Schematic of the multi‐model strategy followed to predict efficacious human dose of the anti‐TGF‐β antibody (GC2008) for the treatment of OI. In the first modeling approach the goal was to predict efficacious dose based on the effect of GC2008 on bone volume fraction (BVF = bone volume/total volume BV/TV). In this, a PK/PD (BVF) relationship was established from 1D11 PK/BVF data in mice. To predict the response for GC2008 in humans, the PK component of the model was replaced to represent GC2008 PK, and the PD parameters governing the half‐life were replaced to represent human bone turnover rate. The model was then used to predict the dose of GC2008 that will lead to a 5% increase in BVF. In the second modeling approach, the goal was to predict the efficacious dose based on the effect of GC2008 on BMD. In this, a PK/PD (BMD) relationship was established from Fresolimumab (GC1008) PK/BMD data. Next, PK data from GC2008 was used along with the Fresolimumab (GC1008) PD‐related parameters to provide a dose that results in a 5% increase in BMD. In the third modeling approach a PBPK model was informed based on drug's physicochemical (PC) properties, TGF‐β levels, and human physiology. After checking the validity of PBPK model's predictions by comparing with GC2008 PK data, the PBPK model was used to evaluate the dose that will decrease OI‐related TGF‐β levels back to their homeostatic concentration. BMD, bone mineral density; CL, clearance; EC₅₀, half‐maximal effective concentration; E _max, maximum effect; OI, osteogenesis imperfecta; PBPK, physiologically‐based pharmacokinetic; PD, pharmacodynamic; PK, pharmacokinetic.

FIGURE 2

Mice 1D11 PK/BVF for different dosing scenarios, and predictions of GC2008 PK/PD response in humans. Shown as concentration versus time (left‐axis), and BVF; (right‐axis) (a) for 5 mg/kg administration three times per week in mice. (b) For 5 mg/kg administration weekly in mice. (c) For 5 mg/kg administration every 2 weeks in mice. (d) For 5 mg/kg administration every 4 weeks in mice. (e) For 0.5 mg/kg administration every 3 months in humans. (f) For 2.5 mg/kg administration every 6 months in humans. Symbols are average BVF data, and error bars depict their SD. Solid lines indicate the model's predictions. BVF, bone volume fraction; PD, pharmacodynamic; PK, pharmacokinetic.

FIGURE 3

PK/BMD response of Fresolimumab (GC1008) in patients with OI shown as concentration versus time (left‐axis), and BMD (right‐axis) response (a) after 1 mg/kg single i.v. administration of Fresolimumab (GC1008). (b) After 4 mg/kg single i.v. administration of Fresolimumab (GC1008). Solid lines represent simulation and symbols human data. BMD, bone mineral density; OI, osteogenesis imperfecta; PK, pharmacokinetic.

FIGURE 4

PK/BMD response of GC2008 shown as concentration vs time (left‐axis), and BMD (right‐axis) response (a) for 0.4 mg/kg i.v. administration of GC2008 every 3 months and (b) for 2 mg/kg i.v. administration of GC2008 every 6 months. BMD, bone mineral density; PK, pharmacokinetic.

FIGURE 5

GC2008 human PBPK model validation and predictions. (a) Concentration of GC2008 for 0.05, 0.25, 1, and 3 mg/kg single i.v. administration. Symbols are individual subject data, and lines depict predictions of PBPK model. (b) Comparison of GC2008 in plasma (solid line) and bone (dotted line) PK for a single i.v. administration of 0.05 mg/kg GC2008. (c) Plasma PK prediction of 0.35 mg/kg administration every 3 months and 2.5 mg/kg administration every 6 months. (d) TGF‐β target dynamics in bone, after 0.35 mg/kg administration every 3 months, or 2.5 mg/kg administration every 6 months of GC2008. Solid lines indicate PBPK model predictions. PBPK, physiologically‐based pharmacokinetic; PK, pharmacokinetic.