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Module 4.2.3 — Toxicology Study Reports (TILA-278)

Field	Value
Document ID	M4-2.3
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH M4S / S6(R1)
Confidentiality	Confidential

Nonclinical study documentation for TILA-278.

Change History

Version	Date	Author	Summary
1.0	2026-07-08	Nonclinical	Initial issue

4.2.3 Toxicology

4.2.3.0 Introduction and Overview of the Toxicology Program

This section presents the toxicology study reports supporting the clinical development and intended marketing of TILA-278, a humanized IgG1 bispecific monoclonal antibody in which one Fab arm antagonizes TL1A (TNFSF15) and the second arm agonizes the interleukin-22 receptor (IL-22R, IL-22RA1/IL-10R2). TILA-278 is administered subcutaneously (SC) and is being developed by Virtual Biopharma Inc. for the induction and maintenance of clinical remission in moderate-to-severe ulcerative colitis (UC). The molecule carries effector-function-attenuating Fc substitutions to avoid Fcγ-receptor– and complement-mediated engagement of target-expressing epithelial and immune cells, consistent with an antagonist/agonist mechanism that does not depend on cytolytic effector activity.

The nonclinical toxicology strategy follows ICH M4S, ICH S6(R1) (Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals), ICH S5(R3) (reproductive toxicity), ICH S1A/S1B (carcinogenicity), and ICH S7A/S7B and S3A (safety pharmacology and toxicokinetics). Because the epitopes engaged by both arms are human-restricted and are not present or not pharmacologically responsive in rodents or other lower species, the cynomolgus monkey (Macaca fascicularis) was identified as the single pharmacologically relevant toxicology species. Target-organ specificity and species relevance were confirmed by a GLP tissue cross-reactivity study (Section 4.2.3.7.1). Pharmacology in disease-relevant models was conducted using a rodent surrogate/knock-in construct and is reported in Module 4.2.1.

All pivotal repeat-dose, local tolerance, reproductive, and tissue cross-reactivity studies were conducted in compliance with Good Laboratory Practice (OECD Principles of GLP; 21 CFR Part 58) and used clinical-representative drug substance/drug product lots. Bioanalytical (TILA-278 concentration) and immunogenicity (anti-drug antibody, ADA) assays were validated prior to sample analysis. The starting dose for first-in-human dosing was set on a Minimal Anticipated Biological Effect Level (MABEL) basis in view of the IL-22R agonist arm (cross-reference Module 2.4 and 2.6.6); the toxicology NOAEL established the upper bound of the exposure margin discussed in Section 4.2.3.8.

Table 4.2.3.0-1. Nonclinical Toxicology Study Inventory

Study No.	Type	Species / System	Route	Duration / Design	GLP
TILA278-TOX-101	Dose-range-finding repeat-dose	Cynomolgus monkey	SC	4 weeks, weekly dosing	Yes
TILA278-TOX-102	Pivotal repeat-dose	Cynomolgus monkey	SC	13 weeks + 4-week recovery	Yes
TILA278-TOX-103	Chronic repeat-dose (pivotal)	Cynomolgus monkey	SC	26 weeks + 8-week recovery	Yes
TILA278-TOX-104	Enhanced pre-/postnatal development (ePPND)	Cynomolgus monkey	SC	GD20 → parturition; infants to PND180	Yes
TILA278-TOX-105	Tissue cross-reactivity	Human + cynomolgus tissue panels	In vitro	FDA standard tissue panel	Yes
TILA278-TOX-106	In vitro cytokine release	Human whole blood / PBMC	In vitro	Soluble + immobilized format	No (exploratory)

Genotoxicity and carcinogenicity studies were not conducted; the scientific rationale for these waivers is provided in Sections 4.2.3.3 and 4.2.3.4. Safety pharmacology endpoints (cardiovascular, respiratory, central nervous system) were integrated into the repeat-dose studies in accordance with ICH S6(R1) (Section 4.2.3.7.3).

4.2.3.1 Single-Dose Toxicity

No dedicated single-dose toxicity study was performed. Consistent with ICH M3(R2) and ICH S6(R1), acute tolerability was characterized within the dose-range-finding study (TILA278-TOX-101) and the initial dosing occasions of the repeat-dose studies. No maximum tolerated dose (MTD) was identified up to the highest dose administered (200 mg/kg SC in the dose-range-finding study); there were no acute clinical signs, no acute injection-associated reactions of concern, and no mortality attributable to TILA-278.

4.2.3.2 Repeat-Dose Toxicity

4.2.3.2.1 Species and Model Justification

The cynomolgus monkey expresses both molecular targets with binding affinity and functional potency comparable to human, and the tissue distribution of TL1A and IL-22RA1 in the cynomolgus tissue panel was concordant with the human panel (Section 4.2.3.7.1). TILA-278 neutralized cynomolgus TL1A and activated cynomolgus IL-22R in vitro with potency within 2-fold of the human targets, establishing the monkey as pharmacologically relevant for both arms of the bispecific. Rodents were not used for toxicology because neither epitope is adequately engaged; a homologous surrogate supported the pharmacology package (Module 4.2.1) but is not appropriate for definitive safety assessment of the clinical molecule.

4.2.3.2.2 Four-Week Dose-Range-Finding Study (TILA278-TOX-101)

Cynomolgus monkeys (3/sex/group) received vehicle or TILA-278 at 30, 100, or 200 mg/kg by weekly SC injection for 4 weeks. TILA-278 was well tolerated at all dose levels. There were no unscheduled deaths, no adverse clinical signs, and no effects on body weight, food consumption, or ophthalmology. Pharmacologically anticipated, non-adverse findings included minimal-to-mild increases in acute-phase reactants (fibrinogen, C-reactive protein) and minimal epidermal and gastrointestinal epithelial changes consistent with IL-22R agonism (described in detail for the pivotal studies below). These results supported selection of 10, 30, and 100 mg/kg/week for the pivotal 13- and 26-week studies with an adequate high-dose exposure multiple.

4.2.3.2.3 Thirteen-Week Pivotal Study (TILA278-TOX-102)

Cynomolgus monkeys (4/sex/group main study; +2/sex in control and high-dose groups for a 4-week recovery phase) received vehicle or TILA-278 at 10, 30, or 100 mg/kg by weekly SC injection for 13 weeks. TILA-278 was clinically well tolerated at all doses. There was no mortality, and no adverse effects on clinical signs, body weight, food consumption, ophthalmology, electrocardiography, or organ weights. The nature and magnitude of clinical-pathology, immunophenotyping, and microscopic findings were consistent with, and of lesser or equal magnitude to, those observed in the 26-week study (Section 4.2.3.2.4). All findings were considered non-adverse and pharmacologically mediated, and all reversed or trended toward baseline during the recovery phase. The NOAEL was the highest dose tested, 100 mg/kg/week.

4.2.3.2.4 Twenty-Six-Week Chronic Study (TILA278-TOX-103)

The 26-week study is the pivotal chronic toxicology study supporting long-term dosing for a chronic indication (UC).

Table 4.2.3.2-1. Design of the 26-Week Chronic Study (TILA278-TOX-103)

Group	TILA-278 dose (SC, weekly)	Main study (M/F)	Recovery (M/F)
1 (Control)	0 (vehicle)	5 / 5	2 / 2
2 (Low)	10 mg/kg	5 / 5	—
3 (Mid)	30 mg/kg	5 / 5	—
4 (High)	100 mg/kg	5 / 5	2 / 2

Dosing was for 26 weeks with an 8-week treatment-free recovery period for control and high-dose animals. Endpoints included mortality, clinical signs, injection-site observations, body weight, food consumption, ophthalmology, safety pharmacology (jacketed cardiovascular telemetry with quantitative ECG, respiratory rate, and a modified functional observational battery), hematology, coagulation, clinical chemistry, urinalysis, peripheral-blood immunophenotyping, a T-cell–dependent antibody response (TDAR), toxicokinetics, ADA, organ weights, and full macroscopic and microscopic pathology.

Mortality and in-life findings. There were no unscheduled deaths. There were no TILA-278–related adverse clinical signs and no effects on body weight, food consumption, or ophthalmology. Safety pharmacology endpoints integrated into the study showed no effects on heart rate, blood pressure, ECG intervals (including no QT/QTc prolongation), respiratory parameters, or neurobehavioral assessments at any dose (cross-reference Section 4.2.3.7.3).

Clinical pathology. Changes were confined to pharmacologically anticipated, minimal-to-mild, reversible effects and were considered non-adverse:

• Minimal-to-mild increases in acute-phase reactants — fibrinogen, C-reactive protein, and serum amyloid A — with a slight associated increase in total globulins, consistent with hepatic IL-22/STAT3 signaling driven by the IL-22R agonist arm. Peak group-mean fibrinogen was increased approximately 1.3–1.6-fold over control at ≥30 mg/kg.
• Minimal increases in circulating neutrophils at 100 mg/kg, consistent with IL-22–induced epithelial chemokine production; no left shift or associated inflammatory pathology.
• No adverse changes in red cell mass, platelets, hepatocellular or cholestatic enzymes (ALT, AST, ALP, GGT, bilirubin), or renal parameters.

All clinical-pathology changes resolved or trended to baseline by the end of the recovery period.

Anatomic pathology and target-organ findings. There were no TILA-278–related organ-weight changes and no adverse microscopic findings. The following microscopic findings were pharmacologically mediated, minimal-to-mild in severity, and fully or partially reversible; each is mechanistically consistent with IL-22R agonism acting on IL-22RA1-expressing epithelia and is therefore not considered adverse:

• Skin/epidermis: minimal-to-mild epidermal hyperplasia (acanthosis) with mild hyperkeratosis at ≥30 mg/kg, without dermal inflammation, erosion, or dysplasia.
• Gastrointestinal tract: minimal increase in mucosal epithelial/crypt cell proliferation with increased goblet-cell mucin at 100 mg/kg, consistent with the intended mucosal-regenerative pharmacology; architecture was preserved, with no dysplasia, erosion, or ulceration.
• Liver: minimal hepatocellular hypertrophy at 100 mg/kg concordant with the acute-phase response; no degeneration, necrosis, or inflammatory infiltrate.
• Injection sites: minimal-to-mild changes described in Section 4.2.3.6.

There were no findings in lymphoid organs, bone marrow, heart, kidney, pancreas, reproductive organs, or central/peripheral nervous tissue that were considered adverse. Importantly, despite the expected regenerative/hyperplastic epithelial changes, no pre-neoplastic, dysplastic, or neoplastic lesions were observed in any tissue after 26 weeks of dosing, and epithelial changes regressed during recovery (relevant to the carcinogenicity assessment in Section 4.2.3.4).

NOAEL. Based on the absence of adverse findings and the reversibility and pharmacological nature of all treatment-related changes, the NOAEL was the highest dose tested, 100 mg/kg/week.

4.2.3.2.5 Immunophenotyping and Immunotoxicology

Given the immunomodulatory mechanism (TL1A/DR3 costimulatory blockade dampening TH1/TH17 responses), immune-system assessment was emphasized. Peripheral-blood immunophenotyping by flow cytometry evaluated major lymphocyte lineages and functional subsets at multiple timepoints and after recovery.

Table 4.2.3.2-2. Peripheral-Blood Immunophenotyping (100 mg/kg, Week 26; direction vs. control)

Population (marker)	Effect	Adversity	Recovery
Total T cells (CD3+)	No meaningful change	Non-adverse	—
Helper T (CD3+CD4+)	Minimal decrease	Non-adverse	Reversible
Cytotoxic T (CD3+CD8+)	No meaningful change	Non-adverse	—
Effector/memory T subset	Minimal-to-mild decrease	Non-adverse (pharmacologic)	Reversible
B cells (CD20+)	No meaningful change	Non-adverse	—
NK cells (CD16+/NKG2A+)	No meaningful change	Non-adverse	—

The minimal reductions in the effector/memory helper-T compartment at the high dose are consistent with reduced DR3 costimulation resulting from TL1A antagonism; they were of small magnitude, not associated with any infectious or lymphoid-organ correlate, and reversible.

A T-cell–dependent antibody response (TDAR) to keyhole limpet hemocyanin was assessed to probe functional immunocompetence. Anti-KLH IgM and IgG responses were preserved at all doses, with no dose-related suppression, indicating that clinically relevant immunosuppression is not anticipated. There were no findings suggestive of opportunistic infection during the studies.

4.2.3.2.6 Toxicokinetics and Anti-Drug Antibodies

Systemic exposure increased with dose across the studied range, with slightly greater-than-dose-proportional increases at the lower doses consistent with target-mediated drug disposition, becoming approximately dose-proportional at the higher doses. There was minimal accumulation with weekly dosing and no marked sex difference.

Table 4.2.3.2-3. Steady-State Toxicokinetics, 26-Week Study (Week 26, sexes combined)

Dose (mg/kg/wk)	Cmax,ss (µg/mL)	AUC0–168h,ss (µg·h/mL)	Cavg,ss (µg/mL)
10	260	30,000	179
30	850	110,000	655
100 (NOAEL)	2,900	403,000	2,400

Anti-drug antibodies were monitored using a validated tiered assay (screening, confirmatory, titer). ADA incidence was low-to-moderate and dose-dependent in its impact on exposure: a subset of low-dose animals developed ADA associated with reduced or declining exposure over time, whereas the majority of high-dose animals maintained sustained exposure through Week 26. Because exposure was maintained at the doses used to define the NOAEL and safety margins, the observed monkey immunogenicity does not compromise the interpretation of the toxicology studies. Anti-drug antibody findings in monkeys are not predictive of human immunogenicity; clinical immunogenicity is characterized in the clinical program (cross-reference Module 2.7.2), where injection-site reactions were the principal drug-attributable clinical finding in the pivotal Phase 2b study TILA278-201.

4.2.3.3 Genotoxicity

No genotoxicity studies were conducted. In accordance with ICH S6(R1), the standard battery of genotoxicity tests described in ICH S2(R1) is neither applicable nor appropriate for a monoclonal antibody. TILA-278 is a large recombinant protein that does not distribute to the nucleus, cannot penetrate the cell to interact directly with DNA or other chromosomal material, and is catabolized to endogenous amino acids and peptides by normal protein-clearance pathways. There are no small-molecule structural alerts. Excipients in the drug product are compendial and qualified, and process-related impurities are controlled by the manufacturing process (Module 3.2.S/3.2.P); none require dedicated genotoxicity qualification. The absence of genotoxicity testing is therefore scientifically justified and consistent with regulatory precedent for therapeutic antibodies.

4.2.3.4 Carcinogenicity

No dedicated carcinogenicity studies (rodent 2-year bioassays or transgenic assays) were conducted. Conventional carcinogenicity testing is not appropriate for TILA-278, consistent with ICH S6(R1) and ICH S1A: the targets are human-restricted so rodents are pharmacologically non-responsive, and the immunogenicity of a human/humanized protein in rodents would preclude the sustained exposure required for a lifetime bioassay. Carcinogenic potential was therefore addressed by a weight-of-evidence assessment.

Two mechanism-based theoretical concerns were evaluated:

1. Proliferative/neoplastic risk from IL-22R agonism. IL-22 drives epithelial proliferation and regeneration via STAT3, which underlies the intended mucosal-healing benefit but also raises a theoretical concern for sustained epithelial proliferation. This concern is mitigated by the following: (i) in the 26-week chronic study, the epithelial changes were limited to minimal-to-mild regenerative hyperplasia without dysplasia, atypia, or neoplasia, and they regressed during recovery; (ii) IL-22R agonism produces a self-limiting, receptor-density-dependent epithelial response rather than unchecked growth; and (iii) exposures far exceeding the intended chronic clinical exposure (Section 4.2.3.8) produced no pre-neoplastic change.
2. Malignancy risk from immunomodulation. As with other agents that dampen TH1/TH17 immunity, a theoretical concern for reduced immune surveillance exists. This is mitigated by the preserved TDAR, the absence of lymphoid depletion or lymphoproliferative findings, the modest and reversible nature of the immunophenotyping changes, and the absence of opportunistic infection in the chronic study.

On the totality of the evidence, dedicated carcinogenicity studies are not warranted; residual theoretical risk will be managed through routine and, as appropriate, targeted pharmacovigilance (cross-reference Module 1.8.2 / Risk Management Plan).

4.2.3.5 Reproductive and Developmental Toxicity

The reproductive toxicity strategy follows ICH S5(R3) and ICH S6(R1) for a human-specific monoclonal antibody, using the cynomolgus monkey as the only relevant species. Because rodents are pharmacologically non-responsive, a full rodent fertility and embryo-fetal battery is not informative; the program instead relies on reproductive-organ assessment within the chronic study and a dedicated enhanced pre- and postnatal development (ePPND) study in monkeys.

4.2.3.5.1 Fertility and Early Embryonic Development

No stand-alone fertility studies were conducted. In accordance with ICH S6(R1), potential effects on reproductive organs were assessed within the 26-week chronic study, which included sexually mature animals. There were no TILA-278–related effects on male or female reproductive organ weights or histopathology (testes, epididymides, prostate, ovaries, uterus, cervix, vagina) at any dose, and menstrual cyclicity in females was unaffected. No adverse effects on fertility parameters are anticipated.

4.2.3.5.2 Embryo-Fetal and Pre-/Postnatal Development (ePPND, TILA278-TOX-104)

An ePPND study was conducted in pregnant cynomolgus monkeys dosed SC weekly from gestation day 20 through parturition, with evaluation of infants through postnatal day 180. Doses were selected to bracket the clinical exposure with a substantial multiple. Endpoints included maternal tolerability, pregnancy maintenance, abortion/embryo-fetal loss, infant survival, growth, external/skeletal/visceral morphology, infant immunophenotyping and TDAR, and maternal and infant TILA-278 concentrations and ADA. Because IgG1 is actively transported across the placenta predominantly in the second and third trimesters, measurable infant exposure at birth was expected and confirmed.

There were no TILA-278–related effects on maternal tolerability, pregnancy maintenance, or the incidence of abortion or embryo-fetal loss, and no increase in external, visceral, or skeletal malformations or variations. Infant survival, growth, and development were unaffected. Infant immune parameters were consistent with the pharmacology of the targets: any minimal changes in infant lymphocyte subsets were small and reversed as circulating TILA-278 was cleared over the postnatal period, and infant TDAR was preserved. The NOAEL for maternal, embryo-fetal, and pre-/postnatal developmental toxicity was the highest dose tested.

4.2.3.5.3 Risk Characterization and Labeling Considerations

Although no developmental toxicity was identified, transplacental transfer of IgG1 in the second half of pregnancy results in fetal/neonatal exposure that could theoretically modulate the developing immune system and IL-22–dependent epithelial/mucosal maturation. Product labeling will reflect the class-based consideration that infants exposed in utero may have detectable circulating antibody for a period after birth, with a corresponding caution regarding administration of live vaccines to such infants until drug has cleared, and a recommendation to weigh benefit against potential risk during pregnancy and lactation. These considerations are integrated into the clinical benefit-risk assessment (cross-reference Module 2.5 and 2.7.4).

4.2.3.6 Local Tolerance

Local tolerance at the intended clinical SC route was evaluated within the repeat-dose monkey studies (13- and 26-week) rather than in a stand-alone study, consistent with ICH S6(R1). Injection sites were observed macroscopically throughout dosing (using a Draize-type scoring approach for erythema and edema) and examined microscopically at necropsy. Findings were limited to minimal-to-mild, transient injection-site reactions — occasional slight erythema in life and minimal-to-mild mixed-cell/mononuclear inflammatory infiltration with associated minimal subcutaneous edema microscopically — occurring at active and, to a lesser extent, vehicle-control sites, indicating a contribution from the injection procedure and formulation as well as the protein. There was no necrosis, and injection-site findings resolved during the recovery period. The clinical-representative drug product formulation (buffer plus polysorbate) was well tolerated locally. These nonclinical findings are consistent with the clinical experience in study TILA278-201, in which injection-site reactions were the principal drug-attributable adverse event and were mild-to-moderate in severity.

4.2.3.7 Other Toxicity Studies

4.2.3.7.1 Tissue Cross-Reactivity (TILA278-TOX-105)

A GLP tissue cross-reactivity study using the standard human tissue panel, with a parallel cynomolgus panel, was conducted with detection reagents specific for the bispecific molecule. Membrane/cytoplasmic staining was consistent with the known distribution of the targets — TL1A associated with vascular endothelium and immune-cell populations, and IL-22RA1 associated with epithelial tissues including skin, gastrointestinal tract, liver, pancreas, kidney, and lung. No unexpected binding to tissues lacking the intended targets was identified, and the human and cynomolgus staining patterns were concordant, supporting both the relevance of the monkey and the absence of off-target tissue binding of toxicological concern.

4.2.3.7.2 In Vitro Cytokine Release (TILA278-TOX-106)

Because the molecule contains an agonist arm, cytokine-release potential was evaluated in human whole-blood and PBMC assays in both soluble and immobilized (plate-bound) formats with appropriate positive controls. TILA-278 did not induce a cytokine-release response indicative of a cytokine-release syndrome risk at concentrations spanning and exceeding the anticipated clinical range, consistent with the effector-attenuated Fc and the targeted, receptor-density-dependent nature of IL-22R agonism.

4.2.3.7.3 Safety Pharmacology (Integrated)

In accordance with ICH S6(R1), core safety-pharmacology endpoints were incorporated into the repeat-dose monkey studies rather than conducted as stand-alone studies. Cardiovascular assessment by jacketed telemetry (heart rate, arterial blood pressure, quantitative ECG including QT/QTc), respiratory rate, and a functional observational battery revealed no TILA-278–related effects at any dose. In particular, there was no QT/QTc prolongation; consistent with ICH E14/S7B principles for large-molecule biotherapeutics that do not interact with cardiac ion channels, a dedicated clinical thorough-QT study is not warranted (cross-reference Module 2.7.2).

4.2.3.8 Derivation of the Human Safety Margin

The human safety margin is derived by comparing systemic exposure at the monkey NOAEL from the pivotal 26-week chronic study (100 mg/kg/week SC; Section 4.2.3.2.4) with the projected steady-state clinical exposure at the highest clinical regimen evaluated in the pivotal Phase 2b study TILA278-201 (TILA-278 High; a 600 mg SC loading dose followed by 300 mg SC at Weeks 2, 4, and 8). Exposure-based margins (AUC and Cmax) are the primary basis for the assessment, in line with ICH S6(R1), because target-mediated disposition and species differences in SC bioavailability make body-weight/dose-based comparisons less reliable; a dose-based margin is provided as a secondary reference. Clinical exposures are cross-referenced to the clinical pharmacology summary (Module 2.7.2).

Table 4.2.3.8-1. Derivation of the Human Safety Margin (Monkey NOAEL vs. Clinical High Regimen)

Parameter	Monkey NOAEL, 100 mg/kg/wk	Clinical High regimen, 600 mg → 300 mg SC	Safety margin
Cmax,ss (µg/mL)	2,900	195	~15×
AUC,ss, weekly-normalized (µg·h/mL)	403,000	23,500	~17×
Cavg,ss (µg/mL)	2,400	140	~17×
Dose (mg/kg/wk equivalent)	100	1.8	~56×

Notes: The AUC margin is computed on a common weekly basis (monkey AUC over the once-weekly dosing interval versus the clinical exposure normalized to a weekly average across the 12-week induction period). The clinical mg/kg/week figure is the average weekly dose over the induction period (total administered dose 1,500 mg — 600 mg loading plus 300 mg at each of Weeks 2, 4, and 8 — across 12 weeks) for a 70-kg patient. All clinical exposure values are pending final population-PK confirmation in Module 2.7.2.

On an exposure basis, the 26-week NOAEL provides an approximately 15-fold (Cmax) to 17-fold (AUC and Cavg) margin over the highest clinical regimen (TILA-278 High), with a substantially larger dose-based margin (on the order of 50-fold) and correspondingly larger margins over the TILA-278 Low regimen (approximately 30-fold on Cmax and 34-fold on AUC). Because the NOAEL was the highest dose tested and all treatment-related monkey findings were minimal, pharmacologically mediated, non-adverse, and reversible, the true safety margin is at least these values. These multiples are considered adequate to support the clinical doses studied and the intended chronic dosing regimen.

4.2.3.9 Integrated Toxicology Conclusion

The nonclinical toxicology program for TILA-278 is complete and appropriate for a humanized IgG1 bispecific antibody administered subcutaneously for a chronic indication, and it conforms to ICH M4S and ICH S6(R1). The cynomolgus monkey was confirmed as the single pharmacologically relevant species by functional cross-reactivity and tissue cross-reactivity data. In pivotal 13-week and 26-week SC studies, TILA-278 was well tolerated with a NOAEL at the highest dose tested (100 mg/kg/week); the only treatment-related findings were minimal-to-mild, reversible, and mechanistically explained by the dual pharmacology — acute-phase and epithelial-regenerative changes from IL-22R agonism, and modest, reversible effector/memory T-cell reductions from TL1A antagonism, with preserved immunocompetence on TDAR. Local tolerance was acceptable, with only minimal-to-mild, reversible injection-site changes concordant with the clinical injection-site reaction profile. Genotoxicity and carcinogenicity testing were appropriately waived, and the mechanism-based proliferative and immunomodulatory carcinogenicity concerns were addressed by weight of evidence. Reproductive and developmental assessments, including an ePPND study, identified no adverse effects, with labeling to reflect class-based transplacental IgG transfer considerations. The NOAEL provides an approximately 15- to 17-fold exposure margin over the highest clinical regimen, supporting the safety of the doses and regimen under clinical evaluation.