Miriam Stuke 1, Martin Fink 1,3, Paul Colbert 2, Stanislav Stoyanov 2, Alexandra Kropotova 2, Christoph Bausch 2, Stefan Wetzel 1
1 Intiquan AG (Basel, Switzerland), 2 SAB Biotherapeutics (Miami Beach, Unites States of America), 3 Boehringer Ingelheim (Vienna, Austria)
Introduction
There is no approved disease-modifying therapy for new-onset Type 1 Diabetes (NOT1D). Although rabbit anti-thymocyte globulin (rATG) is effective at preserving C-peptide and lowering HbA1C, it is limited by safety concerns, including serum sickness and immunogenicity, that prevent redosing. SAB-142, a fully human, multi-specific anti-thymocyte globulin, is designed to delay NOT1D onset and progression with low to no immunogenicity, enabling safe chronic administration (e.g. every 6 months).
C-peptide is a key biomarker of disease progression in T1D. C-peptide and immunophenotyping data from two prior clinical studies¹ ² evaluating rATG at 2.5 and 6.5 mg/kg in T1D patients and immunophenotyping data from the first-in-human study, SAB-142-101, were used to generate an efficacy profile to guide dose selection for SAB-142 a subsequent phase 2b study, SAFEGUARD.
Thus, the objectives of this work were to a) characterize C-peptide changes in T1D patients from two rATG clinical studies START and TN-19, including the influence of covariates, to b) describe the pharmacodynamic (PD) profile of SAB-142 in humans by assessing its dose-dependent dynamics on lymphocyte subtypes in Study SAB-142-101, particularly those related to the slower decline of C-peptide in T1D patients, and to c) provide supportive evidence for the dosing regimen of SAB-142 that is currently being tested in a Phase 2b setting in T1D patients.
Methods
An analysis of C-peptide was conducted in T1D patients receiving rATG or placebo treatment. A longitudinal model of C-peptide decline was developed, relating the slower or faster decline in C-peptide to covariates. The tested covariates included age, weight, sex, baseline lymphocyte count, rATG treatment, and, based on a previous publication, the percentage of exhausted CD4⁺ T cells at baseline and Week 12 (defined by PD1⁺KLRG1⁺CD57⁻CD4⁺), as well as the percentage of CD45RA⁺ non-Treg CD4⁺ T cells at baseline or Week 12³.
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. Immunophenotyping results from FACS data were generated from a static or fixed gating method, which did not account for batch-to-batch variability.
The PD effect of SAB-142 was characterized by an increase in PD1-positive conventional T cells (PD1⁺ Tconv), TIGIT-positive regulatory T cells (TIGIT⁺ Treg), and CD8-positive central memory T cells (CD8⁺ CM) in healthy volunteers was assessed graphically. To assess the dose-response relationship, the area under the effect curve (AUEC) was graphically explored.
Model estimation was carried out using NONMEM v7.5.0 on the R-based IQRtools⁴ platform.
Results
A longitudinal model of C-peptide in T1D patients was developed with age and %exhausted CD4⁺ T cells (defined by PD1⁺KLRG1⁺CD57⁻CD4⁺) as relevant covariates for C-peptide reduction over time. The C-peptide model indicated that with an approximately 75% increase over baseline of %exhausted T cells at Week 12, the C-peptide decline would be reduced by approximately 30% versus placebo, as estimated for the TN-19 study.
The assessment of pharmacodynamic exhaustion markers PD1⁺ Tconv and TIGIT⁺ Treg confirmed a hormetic dose-response relationship, with maximum response observed at 1.5 mg/kg and 2.5 mg/kg treatment, respectively, when considering baseline-normalized AUEC until Day 120. For the PD memory phenotype marker CD8⁺ CM, the maximum response was observed at the respective highest assessed dose at both the 120 Day readout and Day 30, specifically in the 2.5 mg/kg and the 4.5 mg/kg dose groups, respectively.
Conclusions
In a model with a delayed exponential decline to a lower bound of C-peptide, the long-term C-peptide response to treatment could be linked to short-term biomarkers, such as the percentage of exhausted CD4⁺ T cells, at Week 12.
The maximum response based on PD1⁺ Tconv is expected at doses between 0.5 and 2.5 mg/kg.
In conclusion, publicly available databases from prior clinical studies were used to develop a longitudinal model of C-peptide preservation to provide supportive evidence for the dosing regimen of SAB-142 in the Phase 2b SAFEGUARD study.
References:
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 Jacobsen 2023: Jacobsen LM, Diggins K, Blanchfield L, et al. Responders to low-dose ATG induce CD4⁺ T cell exhaustion in type 1 diabetes. JCI Insight. 2023;8(16):e161812. doi:10.1172/jci.insight.161812.
⁴ https://iqrtools.intiquan.com
Reference: PAGE 34 (2026) Abstr 12193 [www.page-meeting.org/?abstract=12193]
Poster: Drug/Disease Modelling - Endocrine