Denis Menshykau 2, Mar Ribera Armengol 1, Faisal Muhammad 1, Celine El-Zein 3, Pinky Dua 1, Akash Khandelwal 2, Rocio Lledo-Garcia 1
1 UCB (Slough, UK), 2 UCB (Monheim am Rhein, Germany), 3 UCB (Brussels, Belgium)
Objectives: For women living with chronic autoimmune diseases, adequate disease control during pregnancy is key to ensure the best maternal and fetal health, and to reduce adverse pregnancy outcomes. Limited information is available on the use of biologics, and specifically the neonatal Fc receptor (FcRn) blocker rozanolixizumab (RLZ), during pregnancy. Due to the crucial role of FcRn in transplacental IgG transfer and the unmet medical need to bring new therapies to this complex population, assessing the effects of the RLZ on IgG reduction in pregnant women and transplacental IgG transfer is warranted. Here we report RLZ pregnancy physiologically based pharmacokinetic (PBPK)-pharmacodynamic (PD) model development and its application to simulate RLZ PK, IgG lowering (PD) and transplacental IgG transfer during pregnancy.
Methods: A base non-pregnant PBPK-PD model was built bottom up in RxODE2 and included endogenous IgG homeostatic system and RLZ challenge to the system based on the well-established framework for PBPK modelling of biologics [1,2]. RLZ mode of action was implemented as high-affinity competitive binding to FcRn. Nonlinear mixed effects modelling was performed in NONMEM 7.5 to inform both population trends and variability based on available RLZ clinical data (UP0018, UP0060, TP0001).
The base non-pregnant PBPK-PD model, developed based on human and cynomolgus monkey data, was extended to include placental and fetal modules. These modules were derived from the base model by integrating allometric scaling and reported physiological changes [3]. The developed pregnancy PBPK-PD model was validated with multiple independent sources of clinical and nonclinical data that were not used during model building. To simulate PK and/or IgG lowering for other IgG-format biologics, FcRn binding constants were set to the values measured in vitro. Finally, the validated pregnancy PBPK-PD model was used to simulate RLZ PK, PD and effect on transplacental IgG transfer during pregnancy.
Results: The base PBPK-PD model adequately captured central tendency as well as variability for observed RLZ PK and PD in non-pregnant healthy volunteers and patients with primary immune thrombocytopenia. The majority of the structural model parameters that were estimated showed good precision (relative standard error ≤ 5%). No notable artifacts were present on diagnostic plots.
To capture observed fetal IgG levels during pregnancy [4,5], it was necessary to increase FcRn expression in the placenta with gestational age, in agreement with the limited experimental data [10]. The pregnancy PBPK-PD model adequately described the external validation datasets: PK of administered IgGs in humans and cynomolgus monkeys; PK of IgG variants with reduced FcRn binding affinity; IgG reduction following RLZ administration in patients with generalized myasthenia gravis (gMG); maternal and fetal IgG levels following RLZ administration in the enhanced pre- and postnatal development study in monkeys [6] and published nipocalimab IgG lowering and transplacental transfer in pregnant women with severe hemolytic disease of the fetus and newborn [7]. The model also adequately captured a recent compassionate use case of RLZ in cardiac neonatal lupus [9]. Based on its ability to capture multiple validation scenarios the pregnancy PBPK-PD model was deemed adequate to explore the effect of RLZ on maternal and fetal IgG levels during pregnancy. Simulations of a hypothetical scenario with the pregnancy PBPK-PD model demonstrated that weekly subcutaneous RLZ dosing starting from the second trimester with the dose body weight tiers approved for patients with gMG [8] resulted in a rapid maternal IgG reduction with the majority of the simulated population achieving at least a 70% reduction in IgG levels. Simulated transplacental IgG transfer was inhibited during RLZ administration, however simulated fetal IgG levels recovered after the stopping of RLZ administration. For a full-term pregnancy of 40 weeks, simulated fetal IgG levels at birth were comparable to those in untreated pregnancies, if the last dose of RLZ was administered at gestational week 32. Simulations demonstrated that in pregnancies with a high likelihood of preterm delivery, termination of RLZ dosing prior to the gestational week 32 would be required to maximize IgG transfer to the fetus.
Conclusion: The developed pregnancy PBPK-PD model informs dosing decisions in this complex population that could benefit from RLZ and informs design characteristics for potential RLZ clinical trials in pregnant women. The model has a potential to be applied to simulate PK and placental transfer of other biologics during pregnancy.
References:
[1] Niederalt C, Kuepfer L, Solodenko J, et al. A generic whole body physiologically based pharmacokinetic model for therapeutic proteins in PK-Sim. J Pharmacokinet Pharmacodyn. 2018 Apr;45(2):235-257. PMID: 29234936.
[2] Hardiansyah D, Ng CM. Two-Pore Minimum Physiologically-based Pharmacokinetic Model to Describe the Disposition of Therapeutic Monoclonal IgG Antibody in Humans. Pharm Res. 2018 Feb 6;35(3):47. PMID: 29411151.
[3] Dallmann A, Ince I, Meyer M, et al. Gestation-Specific Changes in the Anatomy and Physiology of Healthy Pregnant Women: An Extended Repository of Model Parameters for Physiologically Based Pharmacokinetic Modeling in Pregnancy. Clin Pharmacokinet. 2017 Nov;56(11):1303-1330. PMID: 28401479.
[4] Malek A, Sager R, Kuhn P, et al. Evolution of maternofetal transport of immunoglobulins during human pregnancy. Am J Reprod Immunol. 1996 Nov;36(5):248-55. PMID: 8955500.
[5] Ikuta T, Iwatani S, Yoshimoto S. Determination and verification of reference intervals of serum immunoglobulin G at birth. Ann Clin Biochem. 2024 Jul;61(4):319-326. PMID: 38135290.
[6] Cauvin A, Brady K, Cavagnaro J, Luetjens CM. Evaluation of the effect of rozanolixizumab on pregnancy outcomes and pre- and postnatal development in cynomolgus monkeys. Reprod Toxicol. 2025 Mar;132:108823. PMID: 39709064.
[7] Moise KJ Jr, Ling LE, Oepkes D, et al.; UNITY Study Group. Nipocalimab in Early-Onset Severe Hemolytic Disease of the Fetus and Newborn. N Engl J Med. 2024 Aug 8;391(6):526-537. PMID: 39115062.
[8] UCB. RYSTIGGO® (rozanolixizumab-noli) [package insert]. U.S. Food and Drug Administration website. https://www.accessdata.fda.gov/drugsatfda_docs/label/2025/761286s007lbl.pdf. Accessed Jan 22, 2026
[9] Carlucci PM, Masson M, Cuneo BF, et al. Blocking the neonatal Fc receptor as a novel approach to prevent cardiac neonatal lupus: a proof-of-concept study. Ann Rheum Dis. 2026 Jan;85(1):164-171. PMID: 41111019.
[10] Lozano NA, Lozano A, Marini V, et al. Expression of FcRn receptor in placental tissue and its relationship with IgG levels in term and preterm newborns. Am J Reprod Immunol. 2018 Sep;80(3):e12972. PMID: 29745444.
Reference: PAGE 34 (2026) Abstr 11860 [www.page-meeting.org/?abstract=11860]
Poster: Oral: Preclinical and Translational modelling to support drug discovery and development