III-14 giovanni Di Veroli

Bone Remodeling QSP to Guide Clinical Trial Design of WNT pathway inhibitors

Giovanni Y Di Veroli, Susanne Prothon, Ulrika W Hamren, Holly Kimko

AstraZeneca

Objectives: Targeting WNT signalling pathways has emerged as an attractive strategy  to treat multiple diseases, including in oncology. WNT also plays a critical role in bone remodeling and there are available biomarkers to study the effect in clinical trials. Here, a quantitative systems model of bone remodelling was developed to support the design of clinical studies and the understanding of risk benefit profiles of WNT pathway inhibitors.

Methods: Bone biomarkers such as CTX and P1NP provide an opportunity to monitor clinical bone remodeling and target engagement. The Riggs model extension on bone1 does not explicitly contain Wnt ligands and relevant receptors and was found challenging to adapt. We developed a Quantitative Systems Pharmacology (QSP) model based on a mechanistic description of bone cell activities coupled with a multitude of relevant biochemical factors.2 The model, which incorporates a link between Osteoblasts and Osteoclasts activities and bone biomarkers, was calibrated with clinical data. Public data from trials with three drugs3–6 that affect bone remodelling pathways in different ways provided a robust clinical and quantitative basis to predict clinical outcomes of the compound of interest.

 Results: The systems model well captured diverse time-course profiles induced by reference drugs for the bone biomarkers. With a new inhibitor, it was predicted that maximum effect is reached after two to three weeks. Biomarkers level recovery was predicted to require up to thirty days post end of treatment. The model could also predict and contrast biomarkers changes to profiles obtained with other drugs and regimens for which bone fragilization may or may have not been reported (e.g. ETC1594). Based on these predictions, the study duration and a bone biomarker sampling schedule could be determined for a Wnt pathway inhibitor clinical study. The study duration was designed to capture biomarkers changes up to steady state. Biomarkers sampling during treatment and post-treatment was designed to capture biomarkers change and recovery profiles.

Conclusions: A model of bone remodeling based on clinical data was successfully built to study bone biomarkers changes in the context of target engagement for novel WNT pathway inhibitors. Further work will link the model with bone mineralization and safety aspects. This work illustrates the great potential of mechanistic systems modelling to facilitate optimal study design decisions to collect informative biomarker data ahead of larger patient studies.

References

  1. Eudy RJ, Baron KT, Riggs MM. Connecting the Dots?: Linking Osteocyte Activity and Therapeutic Modulation of Sclerostin by Extending a Multiscale Systems Model. 2015;(September):527-536.
  2. Lemaire V, Cox DR. Dynamics of Bone Cell Interactions and Differential Responses to PTH and Antibody-Based Therapies. Bull Math Biol. 2019;81(9):3575-3622.
  3. Padhi D, Jang G, Stouch B, Fang L, Posvar E. Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res. 2011;26(1):19-26.
  4. Ng M, Tan DSP, Subbiah V, et al. First-in-human phase 1 study of ETC-159 an oral PORCN inhbitor in patients with advanced solid tumours. J Clin Oncol. 2017;35(15_suppl):2584.
  5. Bone T, Effects D, Seeman E, et al. J BMR Microarchitectural Deterioration of Cortical and.
  6. Bekker PJ, Holloway DL, Rasmussen AS, et al. A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res.

Reference: PAGE 30 (2022) Abstr 10043 [www.page-meeting.org/?abstract=10043]

Poster: Methodology - Study Design

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