Rocio Lledo Garcia 1, Marcus Björnson 2, Faisal Muhamad 1, Mar Ribera Armengol 1, Virginie Kerbusch 3, Pinky Dua 1
1 UCB (Slough, United Kingdom), 2 Pharmetheus AB (Uppsala, Sweden), 3 PharmAspire BV (Wijchen, Netherlands)
Objectives–Generalised myasthenia gravis (gMG) is an autoimmune disorder caused by IgG antibodies attacking acetylcholine receptor (AChR) or muscle-specific kinase (MuSK), leading to muscle weakness and impaired daily activities. In IgG-mediated diseases, targeting IgG is therapeutically meaningful. The neonatal Fc receptor (FcRn) maintains long IgG half life. Rozanolixizumab, a humanized IgG4P monoclonal antibody, blocks IgG FcRn interaction with high affinity and increases IgG clearance.
This analysis characterised the exposure–response link between IgG lowering and MG-Activities of Daily Living (ADL) improvement and utilize model-informed evidence to support a dose simplification in the rozanolixizumab U.S. label.
IgG reduction was benchmarked across FcRn blockers at various body weights(BWs), using dosing guidelines to show class-level differences.
Methods–Data were integrated across Phase 1-3 studies (UP0018, UP0060, UP0106, TP0001, MG0002, MG0003, and MG0004) (898 rozanolixizumab concentrations; 5566 IgG observations; 2180 MG-ADL observations).
NONMEM 7.4.4 (FOCE-I) was used. The PK model was a one-compartment model with first-order absorption and target-mediated drug disposition (TMDD) via a quasi-equilibrium approximation. An indirect-response model where FcRn-occupancy increased IgG elimination described IgG turnover [1]. MG-ADL was modelled as a continuous, bounded direct-response function driven by percent IgG reduction.
Evaluated covariates included weight, formulation, ADA/NAb status, baseline steroids, demographic factors, hepatic and renal markers, and MG Foundation of America(MGFA) disease class.
For the FcRn blockers comparison, published PK-IgG models for efgartigimod and nipocalimab [2,3] were used and validated against published clinical data in gMG patients [4,5,6,7].
Results
Population PK-IgG
Rozanolixizumab demonstrated nonlinear PK, with elimination dominated by TMDD. Following 6 weekly SC doses, >90% (≈7mg/kg) and >80% (≈10mg/kg) of total drug elimination occurred via FcRn-mediated pathways.
Body weight significantly affected FcRn-independent CL/F and V/F. This translated into ~85% lower Cmax and AUC for 122kg subjects and 3–5-fold higher rozanolixizumab exposure for 46kg subjects relative to 76kg individuals for a same 560mg dose. With minimal impact on IgG reduction, explained by sufficient FcRn-occupancy across BWs. Lower baseline IgG (16.5%) and a higher maximum effect (Emax; 27.1%) was found in patients with baseline steroid usage, resulting in modest increases in IgG (6%) after six doses of 560mg rozanolixizumab QW. ADA/NAb positivity increased FcRn independent CL/F leading to 17% and 24% decrease in Cmax and AUC, respectively for a 560mg dose, but the effect on IgG reduction was small as this clearance makes a minimal contribution to rozanolixizumab elimination.
MG-ADL model
Percent IgG reduction was linearly associated with MG-ADL improvement. Baseline MG-ADL was found to increase with higher MGFA disease class, the only statistically significant covariate found. The model showed excellent performance in internal/external validation.
Model-informed dose simplification
Model simulations supported a dosing regimen simplification to three fixed-dose-tiers in the U.S. Rystiggo label, all administered subcutaneously once weekly for 6 weeks [8]:
• 420mg for patients <50kg
• 560mg for 50–<100kg
• 840mg for ≥100kg
Simulations demonstrated that these fixed-dose-tiers maintain exposure levels and FcRn-occupancy within the therapeutic range and preserved the validated IgG–MG-ADL relationship.
FcRn blockers comparison
Comparison of the 3 approved FcRn blockers for gMG – rozanolixizumab (US.Label), efgartigimod (10mg/kg i.v. QW), and nipocalimab (30mg/kg LoadDose-15mg/kg iv) – through simulations, showed that rozanolixizumab and efgartigimod achieved IgG reductions of 64% vs 75%, 73.5% vs 68.6% and 71% vs 73.4%, for 46kg, 76 kg and 122kg patients, respectively, with efgartigimod requiring more nanomoles. While a defined threshold at which IgG reduction results in clinically meaningful improvement in MG-ADL has not been established, a ~70% IgG reduction (as achieved by plasma-exchange [9]) is considered a target. The duration of IgG reduction with efgartigimod was shorter than rozanolixizumab, which may translate to needing a new cycle earlier.
Nipocalimab also required higher nanomoles than rozanolixizumab to achieve similar IgG reduction. Differences of ~10% on IgG reduction between peaks/troughs showed that IgG reduction was not sustained during the dosing interval and peaks did not consistently reach 70% across BWs.
Conclusions
A population PK/PD model described rozanolixizumab PK, IgG reduction, and MG-ADL response adequately. IgG decreases were sustained across BWs. The covariates affecting the PK had minimal clinical impact on IgG reduction or MG-ADL response. Modelling supported further dosing simplification to three BW-dose-tiers. FcRn blockers were compared through PK/PD modeling, predicting a more stable IgG control across BWs with lower nanomole doses for rozanolixizumab than efgartigimod or nipocalimab in gMG patients.
References:
[1] Lledo-Garcia et al. CPT: Pharmacometrics & System Pharmacology (2022) 11, 116-128.
[2] Valenzuela et al. CPT: Pharmacometrics & System Pharmacology (2025) 14, 2074-2085.
[3] Hoefman et al. J Pharmacokinet Pharmacodyn (2024) 52, 2.
[4] Howard Jr et al. Front Neurol (2024) 14, 1284444.
[5] Habib et al. Ann Clin Transl Neurol (2025) 12, 1162-1170.
[6] Antozzi et al. Neurology (2024) 102, e207937.
[7] Antozzi et al. The Lancet Neurology (2025) 24, 105-116.
[8] https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/761286s000lbl.pdf
[9] Foettinger et al. Int. J. Mol. Sci. (2023)24(7), 6552.
Reference: PAGE 34 (2026) Abstr 11854 [www.page-meeting.org/?abstract=11854]
Poster: Drug/Disease Modelling - Other Topics