Stine Timmermann 1, Jurij Aguiar Zdovc 2,3, Maarten van Eijk 2, Lærke Clement Freiberg 1, Kristin Cecilie Carlsson Petri 1
1 Ascendis Pharma A/S (Hellerup, Denmark), 2 Pharmetheus A/B (Uppsala, Sweden), 3 Faculty of Pharmacy, University of Ljubljana (Ljubljana, Slovenia)
Introduction:
Achondroplasia (ACH) is a rare genetic condition arising from a systemic fibroblast growth factor receptor 3 (FGFR3) variant leading to skeletal dysplasia and serious muscular, neurological, and cardiorespiratory complications. Achondroplasia affects more than 250,000 people worldwide [1, 2].
In bone, FGFR3 acts as a negative regulator of chondrocyte differentiation. In ACH, constitutive activation of FGFR3 leads to sustained downstream signaling, resulting in poor endochondral bone growth and skeletal dysplasia [1, 3, 4]. C-type natriuretic peptide (CNP) is a positive regulator of bone growth that promotes chondrocyte differentiation by inhibiting the FGFR3 signaling pathway [1, 5, 6].
Navepegritide is an investigational prodrug of CNP, administered once weekly (q1w) and designed to provide sustained release and continuous exposure to active CNP to counteract the constitutively active FGFR3. Navepegritide is designed to avoid high peak plasma concentrations of active CNP to prevent the acute hypotensive effects observed historically with administration of exogenous CNP [7, 8]. Navepegritide consists of a CNP moiety identical to the amino acid sequence 89-126 of endogenous CNP transiently linked to an inert methoxypolyethylene glycol (mPEG) carrier via a proprietary TransConâ„¢ linker.
A semi-mechanistic pharmacokinetic (PK) model of navepegritide has previously been developed using data from 35 healthy adults and 42 children with ACH [9].
Objectives:
1) To strengthen the existing PK model with data from 90 additional children and adolescents with ACH and perform external validation with data from 40 children and infants with ACH
2) To explore the active CNP exposure in infants (<2yr) compared to children (≥2yr - <18yr)
3) To explore the relationship between active CNP exposure and annualized growth velocity (AGV)
Methods:
Data from a Phase 1 trial in healthy volunteers (n=35) [10], two Phase 2 trials (n=57 [11], n=24 [12]) and a pivotal trial in children (2-11 years at screening) with ACH (n=84 [13]), an open-label extension trial (n=39 [14]), and a trial in infants (n=7 [15]) with ACH were included either in model development, to validate the model on long-term data or as external validation. The dose-ranging phase 2 trials evaluated subcutaneous doses of navepegritide 6, 20, 50 or 100 µg/kg q1w, and navepegritide 100 µg/kg q1w in the pivotal and open-label extension trials. Navepegritide, mPEG, and active CNP plasma concentrations were measured.
The previously reported PK model [9] was the starting point of model development. The model was updated based on additional longer-term data from the two Phase 2 trials and the pivotal trial in children with ACH. The covariate analysis included time-varying body weight, renal function, sex, race and ethnicity, with dose evaluated separately. Subsequently, the model was validated on long-term extension data and externally validated using data from 33 children with ACH, and 7 infants with ACH receiving navepegritide for up to 1 year.
The exposure-response analysis was conducted by pairing model-predicted individual AUCÏ„,ss of active CNP and AGV at Week 52. Model evaluation included linear, Emax, and sigmoidal Emax models. Exposure following dosing according to weight-based dose bands was simulated and evaluated.
Results:
The PK model was consistent with the previously reported model [9]. Time-varying body weight was the only clinically relevant covariate identified in the analysis. The model accurately described the characteristics of the validation dataset.
During q1w dosing, the administration of navepegritide provided sustained release and continuous exposure to active CNP avoiding high peak concentrations, thereby preventing acute hypotensive effects.
AGV increased with increasing exposure of active CNP and reached a plateau at the steady-state exposure level achieved with navepegritide 100 µg/kg q1w. The exposure-response relationship was best described by a steep sigmoidal Emax model.
Conclusions:
Navepegritide PK in infants, children, and adolescents with ACH was well-characterized by the semi-mechanistic model, showing similar and sustained release of active CNP across age groups and avoidance of high peak plasma concentrations. The PK model, combined with the identified relationship between active CNP exposure and AGV, provides strong supporting evidence for 100 µg/kg/week as the appropriate therapeutic dose of navepegritide. Further, simulations with the PK model support the use of weight-based dose bands to simplify dose administration.
References:
[1] Horton WA et al. Lancet 370(9582):162-172, 2007.
[2] Baujat G et al. Best Pract Res Clin Rheumat 22(1): 3-18, 2008.
[3] Pauli RM Orphanet J Rare Dis 14(1):1, 2019.
[4] Wrobel W et al. Int J Mol Sci 22(11), 2021.
[5] Breinholt VM et al. J Pharmacol Exp Ther 370(3):459-71, 2019.
[6] Rintz E et al. Int J Mol Sci 23(11), 2022.
[7] Igaki T et al. Hypertens Res 21(1): 7-13,1998.
[8] https://www.ema.europa.eu/en/documents/product-information/voxzogo-epar-product-information_en.pdf
[9] Petri KCC et al. PAGE abstract 11219, 2024 [www.page-meeting.org/?abstract=11219].
[10] Breinholt VM et al. Br J Clin Pharmacol 88(11):4763-72, 2022.
[11] Savarirayan R et al. eClinicalMedicine 2;65:102258, 2023.
[12] https://clinicaltrials.gov/study/NCT05246033
[13] Savarirayan R et al. JAMA Pediatr. Jan1;180(1):18-25, 2026.
[14] https://clinicaltrials.gov/study/NCT05929807
[15] https://clinicaltrials.gov/study/NCT06079398
Reference: PAGE 34 (2026) Abstr 12255 [www.page-meeting.org/?abstract=12255]
Poster: Drug/Disease Modelling - Endocrine