Daniel Lill 1,3, Miriam Stuke 1, Martin Fink 1,4, Diego Vera-Yunca 1, Paul Colbert 2, Stanislav Stoyanov 2, Alexandra Kropotova 2, Christoph Bausch 2
1 IntiQuan AG (Basel, Switzerland), 2 SAB Biotherapeutics (Sioux Falls, United States of America), 3 Affiliated with Thermo Fisher since August 2025 (, ), 4 Affiliated with Boehringer Ingelheim since February 2026 (, )
Objectives
Rabbit and horse-derived anti-thymocyte globulin (rATG or hoATG) are established drugs for immunosuppression that are administered following organ transplantation. Studies have evaluated low-dose rATG as a preventative treatment during early onset of Type 1 Diabetes (T1D)¹ ², however, rATG is limited by safety concerns, including serum sickness and immunogenicity, that prevent redosing. SAB-142, a fully human, multi-specific anti-thymocyte globulin has been developed to mitigate safety and immunogenicity concerns, allowing maintenance redosing (e.g. every 6 months).
Type 1 Diabetes (T1D) is an autoimmune disease characterized by the immune system destroying insulin-producing pancreas cells. The onset of T1D can occur throughout life, but is often seen in children or young adults, presenting with more rapid progression than in subjects with later onset. As the disease is not yet curable, the pediatric population could realize the greatest benefit from early preservation of β-cells as they will have the longest disease exposure and therefore are a key population for these immunomodulatory treatments.
The objectives of this analysis were to a) characterize the pharmacokinetics (PK) of free/unbound ‘on-target’ SAB-142 in humans, b) determine age-related effects in PK and pharmacodynamic (PD) markers in non-human primates (NHPs) treated with SAB-142, and c) simulate the PK and PD profiles of SAB-142 in adolescents (12 – <18 years of age) and pediatric (5 - <12 years of age) patient populations.
Methods
The age- and weight-dependent PK and PK/PD relationship of SAB-142 were evaluated to ensure the safety of the patient population in upcoming clinical studies.
A population PK (popPK) approach was implemented to model the PK of SAB-142 in NHPs and humans. The NHP studies included a 28-day acute toxicology study in young adult NHPs and a 9-month chronic toxicology study in juvenile NHPs. The SAB-142 Phase 1 study was a randomized, double-blind, placebo-controlled study that included single-ascending dose cohorts (Part A) in healthy volunteers (HVs) and participants with stable T1D, and a multiple dose cohort (Part B) in HVs that was included to support a 6-month maintenance dosing regimen.
In humans, the PK modeling approach was expanded to a PK/PD model incorporating lymphocyte dynamics observed over time.
Model estimation was carried out using NONMEM v 7.5.0 and the R-based IQRTools³ platform.
Results
SAB-142 had similar PK profiles across pediatric, adolescent, and young adult NHPs, which was further confirmed by the successful application of fixed allometric scaling to a 2-compartment popPK model with linear clearance without the need for further covariates. The PK/PD relationship for lymphocytes and their subsets showed similarity across age groups, thus supporting the modeling assumptions of no age dependence in humans.
The PK/PD model in humans described free/unbound "on-target" SAB-142 concentrations with a linear clearance and two compartments. The lymphocyte dynamics observed in the blood were described by an immediate response with a modulator. The immediate response part represents the decrease of lymphocytes due to margination, while the modulator models the increase of lymphocytes in the blood, caused by their return to peripheral circulation.
Simulations of the vulnerable group of adolescents and children predicted a quick return of lymphocytes to baseline. The simulations were based on the PK/PD model developed on adult data in healthy volunteers, accounting for age-related differences by scaling PK parameters allometrically with bodyweight.
Conclusions
Studies in juvenile and young adult NHP supported the use of standard allometric scaling coefficients in the PK model and suggested no marked difference between the age groups in lymphocyte response to drug treatment.
The structure of the developed PK/PD model aligns with the concept of peripheral homeostasis in contrast to lymphocyte depletion and requires the modulator to model rapid recovery of the lymphocyte signal.
References:
¹ Haller 2018: Haller MJ, Schatz DA, Skyler JS, et al. Low-Dose Anti-Thymocyte Globulin (ATG) Preserves β-Cell Function and Improves HbA1c in New-Onset Type 1 Diabetes. Diabetes Care. 2018;41(9):1917-1925. doi:10.2337/dc18-0494
² Gitelman 2016: Gitelman SE, Gottlieb PA, Felner EI, Willi SM, Fisher LK, Moran A, Gottschalk M, Moore WV, Pinckney A, Keyes-Elstein L, Harris KM. Antithymocyte globulin therapy for patients with recent-onset type 1 diabetes: 2 year results of a randomized trial. Diabetologia. 2016 Jun;59:1153-61.
³ https://iqrtools.intiquan.com
Reference: PAGE 34 (2026) Abstr 11997 [www.page-meeting.org/?abstract=11997]
Poster: Drug/Disease Modelling - Safety