TransCon CNP (Navepegritide): A semi-mechanistic model to describe the prolonged half-life of C-type natriuretic peptide through TransConTM technology
Kristin C. Carlsson Petri (1), Irina-Elena Antonescu (1), Fanny Gallais (2), Ari Brekkan (2)
(1) Ascendis Pharma AS, Denmark, (2) Pharmetheus AB, Sweden
Introduction: Achondroplasia (ACH) is a rare genetic form of skeletal dysplasia associated with a range of clinical manifestations and complications, including disproportionate short stature, spinal deformities, and reduced muscle strength and stamina, impacting health-related quality of life. ACH affects 250,000 individuals worldwide, with equal prevalence across sexes [1]. ACH is caused by a gain-of-function autosomal dominant variant of the fibroblast growth factor 3 receptor (FGFR3) gene. The genetic change results in short stature with reduced length of proximal limbs (rhizomelia). Almost all children with ACH have low muscle strength at birth, which persists to varying degrees during childhood and into adulthood [2 - 4]
C-type natriuretic peptide (CNP) stimulates bone growth via inhibition of the MAPK signalling pathway downstream of FGFR3 in growth plate chondrocytes, mediated through activation of the natriuretic peptide receptor-B (NPR-B) and thereby counteracts the over-activated FGFR3 induced stunted growth in ACH [5]. NPR-B-induced cGMP in skeletal muscles may directly improve functionality.
Navepegritide is a prodrug consisting of a CNP moiety transiently conjugated with an inert methoxypolyethylene glycol (mPEG) carrier via a proprietary TransConTM linker, providing sustained release of active CNP supporting once-weekly dosing. The amino acid sequence of the CNP moiety is identical to the 38 amino acid sequence of residues 89-126 of human CNP. The CNP moiety is inactive when bound to the carrier. Navepegritide releases CNP via auto-cleavage of the linker in a controlled manner following first-order kinetics upon exposure to physiologic pH and temperature.
Previously, semi-mechanistic population PK models have been developed for other compounds using TransCon Technology, with good in vitro-in vivo correlation (IVIVC) between the model-fitted in vivo linker cleavage half-life and the linker cleavage half-life measured in vitro [6].
Objectives: This study aimed to simultaneously characterize the concentration-time course of navepegritide, released CNP and the associated mPEG carrier, to enhance the understanding of drug disposition and optimize dosing strategies in paediatric patients with ACH.
Methods: A semi-mechanistic population PK model was developed to simultaneously characterize the plasma concentrations of navepegritide, released CNP and the associated mPEG carrier, following SC administration of navepegritide. The model was based on data from a Phase I study in healthy, male volunteers (n=35) [7] and a Phase 2 study in pre-pubertal paediatric patients with ACH (n=42, age 2 to 10 years at screening) [8].
Results: The PK of all entities was 1-compartmental with first-order absorption rates from a SC tissue depot compartment, and linear elimination. Irreversible dissociation of the prodrug to free drug and mPEG was assumed to occur both in plasma and the SC tissue depot compartment. Even with sparse sampling over 52 weeks, the average number of observations per participant was 32 in the paediatric trial. The model complexity and dataset structure led to long run times. Model diagnostics for the final model indicated a satisfactory predictive performance for navepegritide, released CNP and mPEG concentrations (especially for the patient population in the paediatric study). Furthermore, this study confirms a good alignment between the linker cleavage half-life fitted in vivo (8.2 days) and the linker cleavage half-life measured in vitro (10±1 days).
Conclusion: The PK and complex interplay between prodrug, free drug, and the mPEG carrier were successfully characterized by a semi-mechanistic PK model, supporting its use to derive individual predictions of exposure and for simulations. The model is being used to support the further development in younger and older paediatric populations with ACH and can be used to inform future studies in adults. The good alignment between the in vitro and in vivo linker cleavage half-lives can support future translational efforts to predict the concentration-time course of prodrug and active drug when clinical PK data is not yet available. The model developed for navepegritide may support clinical trial design, dose optimization, and life-cycle management, as well as the prediction of human PK for new TransCon drug candidates.
References:
[1] Horton, W. A., J. G. Hall and J. T. Hecht (2007). "Achondroplasia." Lancet 370(9582): 162-172.
[2] Pauli, R. M. (2019). "Achondroplasia: a comprehensive clinical review." Orphanet J Rare Dis 14(1): 1.
[3] Sims, D. T., G. L. Onambele-Pearson, A. Burden, et al. (2018). "Specific force of the vastus lateralis in adults with achondroplasia." J Appl Physiol (1985) 124(3): 696-703.
[4] U.S. Food & Drug Administration. Minutes of a Joint Meeting of the Pediatric Advisory Committee and the Endocrinologic and Metabolic Drugs Advisory Committee. https://www.fda.gov/media/114640/download
[5] Miyazawa, T., Y. Ogawa, H. Chusho, et al. (2002). "Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification." Endocrinology 143(9): 3604-3610
[6] Vollmer J. (2022), Population PK of TransCon PTH in healthy and in subjects with hypoparathyroidism in trials CT-103, TCP-104, TCP-105, TCP-201 and TCP-304. LYO-X AG, on file.
[7] Breinholt VM, Mygind PH, Christoffersen ED, et al. (2022). Phase 1 safety, tolerability, pharmacokinetics and pharmacodynamics results of a long-acting C-type natriuretic peptide prodrug, TransCon CNP. Br J Clin Pharmacol. 88(11): 4763-4772.
[8] Savarirayan R., Hoernschemeyer, D.G., Ljungberg M. (2023), Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial. EClinicalMedicine, 2; 65:102258
