Module 2.6 — Nonclinical Written & Tabulated Summaries (TILA-278)
📚 Part of the TILA-278 Regulatory Dossier — Reader's Guide. This article shows the live document; edits to the source appear here automatically.
This is a mock / simulation document, made for a portfolio and for learning. The drug (GLPI-103), the sponsor, the people, and the data are all fictional. It is not a real regulatory submission and has no clinical, legal, or regulatory standing. What is real is the shape of the thing — the document structure, the standards it follows, and the analysis methods; the content inside is illustrative.
What it is. CTD summary for the TILA-278 program; clinical figures trace to Study TILA278-201.
Why it exists. A high-level CTD summary a reviewer reads first; it distils the underlying reports.
How it is produced here. It contains no new data. It is a distillation — it gathers, summarizes, and cross-references the underlying study reports and datasets into the shorter form a regulator reads first.
Format & governing standard. ICH M4S
Module 2.6 — Nonclinical Written & Tabulated Summaries (TILA-278)
| Field | Value |
|---|---|
| Document ID | M2.6 |
| Version | 1.0 |
| Compound | TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific) |
| Standard | ICH M4S |
| Confidentiality | Confidential |
CTD summary for the TILA-278 program; clinical figures trace to Study TILA278-201.
Change History
| Version | Date | Author | Summary |
|---|---|---|---|
| 1.0 | 2026-07-08 | Clinical/Regulatory | Initial issue |
2.6.1 Introduction
This document comprises the Nonclinical Written and Tabulated Summaries (Module 2.6) for TILA-278, covering the nonclinical pharmacology, pharmacokinetics, and toxicology program conducted by Virtual Biopharma Inc. in support of TILA-278 for the treatment of moderate-to-severe ulcerative colitis (UC). The summaries are organized in accordance with ICH M4S(R2) and cross-reference the integrated assessment presented in the Nonclinical Overview (Module 2.4).
Test article. TILA-278 is a recombinant, humanized IgG1(κ) bispecific monoclonal antibody (approximate molecular mass 148 kDa) produced in a Chinese hamster ovary (CHO) cell line and administered subcutaneously (SC). The molecule is a heterodimeric knob-into-hole construct in which one antigen-binding arm is a high-affinity antagonist of TL1A (TNFSF15) and the second arm is an agonist of the IL-22 receptor (IL-22RA1/IL-10RB). The Fc region is engineered on an effector-attenuated IgG1 backbone to minimize Fcγ-receptor– and complement-mediated effector function, consistent with a mechanism in which neither target-bearing cell populations nor IL-22R–expressing epithelium are intended to be depleted.
Rationale for the nonclinical strategy. The pharmacological rationale combines TL1A antagonism—which dampens TH1/TH17-driven mucosal inflammation and intestinal fibrosis—with IL-22R agonism—which drives intestinal epithelial regeneration and mucosal-barrier repair. Because both epitopes are human-specific and TILA-278 does not bind rodent orthologues, classical rodent species are not pharmacologically relevant. Consistent with ICH S6(R1), the nonclinical program therefore relies on: (i) in vitro characterization of both binding activities and in vivo pharmacology using a murine surrogate bispecific in established colitis models; (ii) the cynomolgus monkey as the single pharmacologically relevant species for repeat-dose SC toxicology, integrated safety pharmacology, and toxicokinetics (TK); and (iii) a GLP tissue cross-reactivity (TCR) assessment in human and cynomolgus tissues. In line with ICH S6(R1), standard genotoxicity and carcinogenicity studies were not conducted; a scientific justification is provided in Sections 2.6.6.4 and 2.6.6.5. A dedicated thorough QT study is not warranted for a monoclonal antibody (ICH E14/S7B Q&A); cardiovascular endpoints were captured within the pivotal repeat-dose study.
All pivotal safety studies were conducted in compliance with GLP regulations (21 CFR Part 58; OECD Principles of GLP). Study identifiers referenced in this module are listed in Section 2.6.7.
2.6.2 Pharmacology Written Summary
2.6.2.1 Brief Summary
TILA-278 is a bispecific antibody engineered to simultaneously (1) neutralize TL1A, thereby blocking TL1A–DR3 (death receptor 3, TNFRSF25) signaling and downstream NF-κB activation in T cells and innate lymphoid cells, and (2) agonize the IL-22 receptor complex on intestinal epithelial cells, driving STAT3 phosphorylation and expression of regenerative and antimicrobial gene programs (e.g., REG3 family, mucins, antimicrobial peptides). In vitro, both arms bound their respective human and cynomolgus targets with sub-nanomolar to low-nanomolar affinity/potency and no measurable binding to rodent orthologues. In vivo, a murine surrogate bispecific (msTILA-278) produced dose-dependent reductions in disease activity and histopathology in two mechanistically distinct mouse colitis models, with concurrent evidence of restored epithelial integrity. Secondary pharmacodynamic evaluation, including an in vitro cytokine-release assessment, revealed no unexpected off-target or agonistic pro-inflammatory activity. Safety pharmacology endpoints (cardiovascular, respiratory, central nervous system) were incorporated into the pivotal 13-week cynomolgus study and showed no test-article-related effects.
2.6.2.2 Primary Pharmacodynamics
Target binding and species cross-reactivity (in vitro). Binding of TILA-278 to soluble human and cynomolgus TL1A and to human and cynomolgus IL-22RA1 was characterized by surface plasmon resonance (SPR) and cell-based assays. The anti-TL1A arm bound human TL1A with an equilibrium dissociation constant (K_D) of 0.18 nM and cynomolgus TL1A with K_D of 0.25 nM. The IL-22R agonist arm engaged the human receptor with an EC50 of 0.9 nM and the cynomolgus receptor with EC50 of 1.3 nM in an epithelial STAT3-phosphorylation reporter assay. No specific binding to murine or rat TL1A or IL-22RA1 was detected, establishing the requirement for a homologous murine surrogate for in vivo disease-model pharmacology.
Functional antagonism (TL1A arm). In a DR3-reporter and primary human T-cell system, TILA-278 neutralized TL1A-induced NF-κB activation and TL1A-costimulated IFN-γ/IL-17 production with an IC50 of approximately 0.4 nM, comparable to a benchmark monospecific anti-TL1A antibody, confirming that bispecific formatting did not compromise antagonist potency.
Functional agonism (IL-22R arm). In human intestinal epithelial cell lines (e.g., Colo205/HT-29), TILA-278 induced STAT3 phosphorylation and dose-dependent expression of REG3A, REG3G, and antimicrobial/mucin transcripts with potency comparable to recombinant human IL-22, and drove epithelial monolayer wound closure in a scratch/barrier assay. Simultaneous dual engagement was confirmed in a bridging assay demonstrating that a single TILA-278 molecule can concurrently capture TL1A and engage IL-22RA1.
In vivo disease-model pharmacology (murine surrogate). Because TILA-278 does not bind rodent targets, in vivo efficacy pharmacology was performed with a homologous murine surrogate bispecific (msTILA-278) in two complementary, mechanistically distinct models:
- Dextran sulfate sodium (DSS)-induced acute colitis (mouse). SC msTILA-278 produced dose-dependent reductions in disease activity index (DAI), attenuated body-weight loss, and reduced colonic histopathology (inflammation, crypt damage) versus vehicle. Colonic pro-inflammatory cytokines (TNF, IL-6, IL-17A) were reduced and epithelial regenerative markers (Reg3γ) increased; intestinal permeability (FITC-dextran flux) was improved.
- Adoptive CD4⁺CD45RB^high T-cell transfer colitis (mouse). SC msTILA-278 dosed therapeutically reduced weight loss, colon-weight/length ratio, and histopathology scores relative to vehicle, with reductions in TH1/TH17 effector cytokines.
Across both models the combined anti-inflammatory (TL1A antagonism) and mucosal-healing (IL-22R agonism) actions were greater than either monospecific control arm alone, supporting the complementary dual-mechanism hypothesis underpinning the clinical program (Protocol TILA278-201).
2.6.2.3 Secondary Pharmacodynamics
Off-target binding was assessed by a membrane-proteome/receptor-array screen and by the GLP tissue cross-reactivity study (Section 2.6.6.8); no unexpected specific off-target binding was identified. An in vitro cytokine-release assay in human whole blood and isolated PBMC (soluble- and plate-immobilized formats) produced no clinically meaningful cytokine release relative to positive controls, consistent with the effector-attenuated Fc and the non–T-cell-crosslinking design. No secondary agonism of DR3 by the antagonist arm and no pro-inflammatory epithelial signaling attributable to IL-22R agonism beyond the expected regenerative program were observed.
2.6.2.4 Safety Pharmacology
In accordance with ICH S6(R1), safety pharmacology endpoints were incorporated into the pivotal repeat-dose toxicity study in cynomolgus monkeys (Study TILA278-TOX-002; Section 2.6.6.3) rather than conducted as stand-alone studies:
- Cardiovascular: quantitative electrocardiography (including QT with Fridericia and Bazett correction), heart rate, and arterial blood pressure. No test-article-related changes in ECG waveform, heart rate, blood pressure, or QTc were observed at any dose up to 100 mg/kg/week.
- Respiratory: respiratory rate and clinical observation of respiratory function; no test-article-related effects.
- Central nervous system: detailed clinical/neurobehavioral observations (modified functional observational battery); no test-article-related effects.
A hERG/ion-channel assay and a dedicated thorough QT study were not conducted; large monoclonal antibodies do not distribute intracellularly or interact with cardiac ion channels, and a QT liability is not mechanistically plausible (ICH E14/S7B Q&A waiver rationale).
2.6.2.5 Pharmacodynamic Drug Interactions
No dedicated nonclinical pharmacodynamic drug-interaction studies were conducted. The two pharmacophores of TILA-278 act on distinct, complementary pathways (TL1A antagonism and IL-22R agonism) engineered into a single molecule; there is no separate co-administered agent requiring interaction assessment at the nonclinical stage.
2.6.2.6 Discussion and Conclusions
The pharmacology package establishes that TILA-278 is a potent, selective bispecific antibody that antagonizes TL1A and agonizes the IL-22 receptor with sub-nanomolar to low-nanomolar activity against human and cynomolgus targets and no rodent cross-reactivity. In vivo, a murine surrogate reproduced the intended dual mechanism—suppression of TH1/TH17 inflammation together with epithelial regeneration and barrier repair—in two independent colitis models. Secondary pharmacodynamic and safety pharmacology evaluations identified no off-target liability and no cardiovascular, respiratory, or CNS concern. Collectively, these data support the pharmacological rationale for the clinical evaluation of TILA-278 in moderate-to-severe UC and confirm the cynomolgus monkey as the relevant species for safety assessment.
2.6.2.7 Tables and Figures
Representative tabulations are provided in Section 2.6.3.
2.6.3 Pharmacology Tabulated Summary
Table 2.6.3-1. Primary pharmacodynamics — in vitro binding and functional activity
| Parameter | Assay / system | Human | Cynomolgus | Rodent |
|---|---|---|---|---|
| Anti-TL1A binding, K_D | SPR (soluble TL1A) | 0.18 nM | 0.25 nM | No binding |
| TL1A neutralization, IC50 | DR3 reporter / primary T cell | 0.4 nM | ~0.5 nM | Not applicable |
| IL-22R agonism, EC50 | Epithelial pSTAT3 reporter | 0.9 nM | 1.3 nM | No activity |
| Dual engagement | Bridging (simultaneous capture) | Confirmed | Confirmed | Not applicable |
Table 2.6.3-2. Primary pharmacodynamics — in vivo efficacy (murine surrogate msTILA-278)
| Study | Model / species | Route / regimen | Key result |
|---|---|---|---|
| TILA278-PH-101 | DSS-induced colitis / mouse | SC, dose-ranging | Dose-dependent ↓ DAI, ↓ histopathology, ↓ colonic TNF/IL-6/IL-17A, ↑ Reg3γ, improved barrier |
| TILA278-PH-102 | CD4⁺CD45RB^hi transfer colitis / mouse | SC, therapeutic | ↓ weight loss, ↓ colon-weight/length, ↓ histopathology, ↓ TH1/TH17 cytokines |
Table 2.6.3-3. Safety pharmacology (integrated into Study TILA278-TOX-002, cynomolgus)
| Organ system | Endpoints | Finding (up to 100 mg/kg/week SC) |
|---|---|---|
| Cardiovascular | ECG, QT/QTc (Fridericia, Bazett), HR, blood pressure | No test-article-related effects |
| Respiratory | Respiratory rate, clinical function | No test-article-related effects |
| Central nervous system | Modified functional observational battery | No test-article-related effects |
2.6.4 Pharmacokinetics Written Summary
2.6.4.1 Brief Summary
The nonclinical pharmacokinetics (PK) and toxicokinetics (TK) of TILA-278 were characterized in cynomolgus monkeys, the pharmacologically relevant species, following single and repeat SC administration. TILA-278 exhibited PK typical of an IgG1 monoclonal antibody superimposed on target-mediated drug disposition (TMDD): absorption with a maximum concentration 2–3 days post-dose, a small volume of distribution approximating plasma/extracellular volume, elimination by proteolytic catabolism rather than renal/hepatic clearance of intact protein, and a terminal half-life of approximately 9–12 days. Systemic exposure increased in a greater-than-dose-proportional manner at low doses (reflecting saturable target-mediated clearance) and approached dose-proportionality at the higher doses used in toxicology. Absolute SC bioavailability was approximately 68%. Anti-drug antibodies (ADA) were detected in a subset of animals and, when present at high titer, were associated with reduced exposure in individual animals; group-mean TK were adequate to support interpretation of the toxicology findings.
2.6.4.2 Methods of Analysis
Serum concentrations of TILA-278 were quantified using validated ligand-binding (ELISA-type) assays: a total-antibody method (target-independent capture of the humanized IgG framework) and an active-antibody method employing target capture to confirm functional bivalency. ADA were assessed with a tiered strategy (screening, confirmatory, titer) using an electrochemiluminescence bridging assay, with a validated drug-tolerance limit and neutralizing-antibody characterization for high-titer samples. Bioanalytical methods were validated for precision, accuracy, selectivity, and matrix effects consistent with FDA/ICH bioanalytical method validation guidance.
2.6.4.3 Absorption
Following single SC administration in cynomolgus monkeys (Study TILA278-PK-001), the time to maximum concentration (T_max) was 48–72 h and absolute SC bioavailability was approximately 68% relative to IV administration. Exposure (C_max, AUC) increased more than dose-proportionally across the low dose range, consistent with saturable TMDD, and approached dose-proportionality over the dose range used in repeat-dose toxicology. Repeat weekly SC dosing produced accumulation consistent with the terminal half-life, reaching steady state by approximately Week 6–8.
2.6.4.4 Distribution
The volume of distribution at steady state (V_ss) was approximately 70 mL/kg, indicating distribution largely confined to the plasma and interstitial (extracellular) space, as expected for a ~148 kDa IgG. Tissue distribution studies with radiolabeled antibody were not conducted; for a monoclonal antibody, disposition is governed by convective/pinocytotic uptake and FcRn-mediated recycling rather than by classical tissue partitioning, and dedicated distribution studies are not scientifically warranted (ICH S6(R1)). Target-expressing tissues relevant to distribution and pharmacology were addressed by the tissue cross-reactivity study (Section 2.6.6.8).
2.6.4.5 Metabolism
Consistent with its proteinaceous nature, TILA-278 is expected to be eliminated by catabolism into small peptides and amino acids that are reutilized or excreted; it is not a substrate for cytochrome P450 enzymes and does not generate discrete small-molecule metabolites. Accordingly, metabolite identification and characterization studies were not conducted (ICH S6(R1)).
2.6.4.6 Excretion
Intact TILA-278 is not expected to undergo appreciable renal or biliary excretion owing to its molecular size; elimination is via intracellular proteolytic catabolism. Dedicated excretion (mass-balance) studies were not conducted and are not scientifically warranted for a monoclonal antibody.
2.6.4.7 Pharmacokinetic Drug Interactions
TILA-278 is not metabolized by, and does not inhibit or induce, cytochrome P450 enzymes or drug transporters; classical PK drug-interaction studies are not applicable. A theoretical cytokine-mediated interaction (disease-state modulation of CYP via inflammatory cytokines) is addressed by the clinical pharmacology program (Module 2.7) rather than nonclinically.
2.6.4.8 Other Pharmacokinetic Studies
Toxicokinetics. TK were integrated into the repeat-dose toxicology studies (Section 2.6.7). Exposure increased with dose across 10–100 mg/kg/week, with modest accumulation on repeat dosing and no marked sex difference.
Immunogenicity (animal). ADA were detected in a subset of cynomolgus monkeys across the repeat-dose studies. ADA were generally low-to-moderate titer; in the minority of animals with high-titer ADA, individual exposures were reduced at later time points. Group-mean exposures remained sufficient to maintain pharmacologic coverage and to support NOAEL determination. Animal immunogenicity is not predictive of human immunogenicity and is used here only to aid interpretation of the toxicology data.
2.6.4.9 Discussion and Conclusions
The nonclinical PK/TK of TILA-278 are those of a typical IgG1 monoclonal antibody with a TMDD component at low exposures: incomplete-but-good SC bioavailability, limited (extracellular) distribution, catabolic elimination, and a multi-day terminal half-life supporting infrequent SC dosing. Exposure data from the toxicology studies establish adequate multiples over the anticipated clinical exposure (Section 2.6.6.9) and, together with the ADA data, support interpretation of the safety findings. No metabolism, excretion, or classical drug-interaction studies were warranted for this modality.
2.6.4.10 Tables and Figures
Representative tabulations are provided in Section 2.6.5.
2.6.5 Pharmacokinetics Tabulated Summary
Table 2.6.5-1. Bioanalytical methods
| Analyte | Method | Matrix | Notes |
|---|---|---|---|
| TILA-278 (total) | Ligand-binding (ELISA), framework capture | Cyno serum | Validated per FDA/ICH BMV |
| TILA-278 (active) | Ligand-binding, target capture | Cyno serum | Confirms functional bivalency |
| ADA | ECL bridging, tiered (screen/confirm/titer) + NAb | Cyno serum | Drug-tolerant format |
Table 2.6.5-2. Single-dose SC pharmacokinetics in cynomolgus monkey (Study TILA278-PK-001)
| Parameter | Value |
|---|---|
| T_max | 48–72 h |
| Absolute SC bioavailability (F) | ~68% |
| Terminal t½ | 9–12 days |
| Clearance (CL) | ~0.20 mL/h/kg |
| V_ss | ~70 mL/kg |
| Dose-proportionality | Greater-than-proportional at low dose (TMDD); ~proportional at high dose |
Table 2.6.5-3. Repeat-dose toxicokinetics — Day 92 (Week 13), Study TILA278-TOX-002 (sexes combined)
| Dose (mg/kg/week SC) | C_max (µg/mL) | AUC0–168h (µg·h/mL) | Accumulation ratio |
|---|---|---|---|
| 10 | 290 | 34,000 | ~2.1 |
| 30 | 880 | 105,000 | ~2.3 |
| 100 | 2,850 | 355,000 | ~2.4 |
2.6.6 Toxicology Written Summary
2.6.6.1 Brief Summary
The toxicology program for TILA-278 was conducted in the cynomolgus monkey, the sole pharmacologically relevant species, and comprised a 4-week dose-range-finding SC study, a pivotal 13-week GLP repeat-dose SC study with an 8-week recovery phase (incorporating safety pharmacology, immunophenotyping, TK, and ADA), and a GLP tissue cross-reactivity study in human and cynomolgus tissues, with local tolerance at SC injection sites evaluated within the repeat-dose studies. TILA-278 was well tolerated at all doses tested. In the pivotal study, the no-observed-adverse-effect level (NOAEL) was the highest dose evaluated, 100 mg/kg/week. Findings were limited to non-adverse, pharmacologically anticipated, and reversible changes (e.g., minimal injection-site reactions and mild epithelial/acute-phase changes consistent with IL-22R agonism). Consistent with ICH S6(R1), genotoxicity and carcinogenicity studies were not conducted. An enhanced pre- and post-natal development (ePPND) study in cynomolgus monkeys is in progress to support later development.
2.6.6.2 Single-Dose Toxicity
A stand-alone single-dose toxicity study was not conducted. Acute tolerability was assessed as part of the 4-week dose-range-finding study (Section 2.6.6.3) and the single-dose PK study (TILA278-PK-001), in which no acute test-article-related toxicity was observed following SC doses up to 200 mg/kg.
2.6.6.3 Repeat-Dose Toxicity
Study TILA278-TOX-001 — 4-week dose-range-finding SC study (cynomolgus, GLP). Groups of cynomolgus monkeys (3/sex/group) received vehicle or TILA-278 at 30, 100, or 200 mg/kg once weekly by SC injection for 4 weeks. There were no unscheduled deaths, no test-article-related clinical signs, and no effects on body weight, food consumption, clinical pathology, organ weights, or histopathology considered adverse. Minimal injection-site changes were observed. The NOAEL was 200 mg/kg/week. These data supported dose selection for the pivotal study.
Study TILA278-TOX-002 — 13-week repeat-dose SC study with 8-week recovery (cynomolgus, GLP; pivotal). Cynomolgus monkeys (5/sex/group main study; additional 3/sex in control and high-dose groups for recovery) received vehicle or TILA-278 at 10, 30, or 100 mg/kg once weekly by SC injection for 13 weeks (14 doses), followed by an 8-week treatment-free recovery period for control and high-dose animals. Endpoints included mortality/moribundity, clinical signs, body weight, food consumption, ophthalmology, cardiovascular and respiratory safety pharmacology, neurobehavioral observations, hematology, coagulation, clinical chemistry, urinalysis, immunophenotyping (peripheral T/B/NK subsets), serum cytokines/acute-phase proteins, TK, ADA, gross necropsy, organ weights, full histopathology, and evaluation of SC injection sites.
Results. There were no test-article-related deaths and no adverse clinical signs. There were no test-article-related effects on body weight, food consumption, ophthalmology, ECG/QTc, heart rate, blood pressure, respiratory rate, or neurobehavioral endpoints. Test-article-related findings were non-adverse and pharmacologically anticipated:
- Injection-site reactions: minimal-to-mild, occasionally with minimal mononuclear-cell infiltration on histopathology; fully reversible by the end of recovery.
- Epithelial/acute-phase changes (IL-22R agonism-related): minimal, reversible increases in acute-phase reactants (e.g., C-reactive protein) and minimal epidermal/mucosal epithelial hyperplasia at higher doses, consistent with the intended IL-22R agonist pharmacology and without associated degeneration, necrosis, or functional impairment.
- Immunophenotyping/immune parameters: no adverse alterations in peripheral lymphocyte subsets; no evidence of clinically meaningful immunosuppression or increased incidence of infection.
All findings were reversible or reversing by the end of the 8-week recovery period. Based on the absence of adverse effects at the highest dose, the NOAEL was 100 mg/kg/week. See Table 2.6.5-3 for corresponding exposures.
2.6.6.4 Genotoxicity
Genotoxicity studies were not conducted. In accordance with ICH S6(R1), the standard battery of genotoxicity assays is not appropriate for a large, target-specific monoclonal antibody, which does not interact directly with DNA or other chromosomal material and is catabolized to endogenous amino acids. No genotoxicity concern is anticipated.
2.6.6.5 Carcinogenicity
Carcinogenicity studies were not conducted. Consistent with ICH S6(R1) and S1A, conventional rodent bioassays are not scientifically valuable or feasible for a human-specific monoclonal antibody with no rodent cross-reactivity. A weight-of-evidence carcinogenicity assessment addressing the biology of TL1A antagonism and IL-22R agonism (including theoretical considerations regarding chronic epithelial proliferation) is provided in the Nonclinical Overview (Module 2.4); no dedicated carcinogenicity study is warranted at this stage.
2.6.6.6 Reproductive and Developmental Toxicity
Dedicated fertility and early-embryonic and embryo-fetal development studies in a non-relevant species are not informative for a human-specific antibody. Male and female reproductive organs were evaluated histologically in the 13-week study (TILA278-TOX-002) with no test-article-related findings. Because IgG1 antibodies undergo FcRn-mediated placental transfer during the second half of gestation, an enhanced pre- and post-natal development (ePPND) study in cynomolgus monkeys (Study TILA278-TOX-004) is in progress to characterize potential effects on pregnancy, parturition, and offspring development; results will be submitted when available. Appropriate contraception requirements are implemented in the clinical program (Protocol TILA278-201) pending completion of the ePPND study.
2.6.6.7 Local Tolerance
Local tolerance was evaluated as an integral component of the repeat-dose SC studies rather than as a stand-alone study. In Study TILA278-TOX-002, SC injection sites showed only minimal-to-mild, reversible reactions with occasional minimal mononuclear infiltration and no necrosis; findings were consistent with SC administration of a protein therapeutic and were not adverse. This nonclinical profile is consistent with the clinical observation that injection-site reactions were the principal drug-attributable finding in the SC-treated arms of TILA278-201.
2.6.6.8 Other Toxicity Studies
Tissue cross-reactivity (Study TILA278-TOX-003, GLP). Immunohistochemical binding of TILA-278 was evaluated on a full panel of frozen normal human tissues (≥32 tissues per FDA guidance) and a corresponding cynomolgus tissue panel, using labeled TILA-278 with appropriate specificity, positive, and negative controls. Membrane/cytoplasmic staining was observed in tissues consistent with the known distribution of the targets—including epithelial staining (e.g., gastrointestinal tract, skin, and other IL-22RA1-expressing epithelia) and staining of mononuclear/endothelial elements consistent with TL1A expression. No unexpected staining suggestive of off-target binding was identified. The concordance between human and cynomolgus staining patterns further supports the cynomolgus monkey as the relevant toxicology species.
Immunotoxicity. Immune-function-relevant endpoints (immunophenotyping, cytokines/acute-phase proteins, lymphoid-organ histopathology, and clinical monitoring for infection) were incorporated into the 13-week study; no adverse immunotoxicity or unexpected immunostimulation/immunosuppression was identified. The in vitro cytokine-release assessment (Section 2.6.2.3) showed no meaningful cytokine release.
2.6.6.9 Discussion and Conclusions
TILA-278 demonstrated a favorable nonclinical safety profile. In the pivotal 13-week GLP SC study in cynomolgus monkeys, TILA-278 was well tolerated with a NOAEL at the highest dose tested (100 mg/kg/week); test-article-related findings were limited to non-adverse, reversible, pharmacologically anticipated changes (minimal injection-site reactions and mild epithelial/acute-phase changes consistent with IL-22R agonism), with no cardiovascular, respiratory, CNS, or immunotoxicity concerns. Tissue cross-reactivity revealed target-consistent binding without off-target liability and reinforced species relevance. Genotoxicity and carcinogenicity studies were appropriately omitted per ICH S6(R1), and reproductive assessment is being completed via an ongoing cynomolgus ePPND study.
Based on the NOAEL exposure (Study TILA278-TOX-002, 100 mg/kg/week) and the projected clinical exposure at the high clinical dose evaluated in TILA278-201, the estimated safety margins are approximately 30-fold on an AUC basis and ~18-fold on a C_max basis. These margins, together with the reversibility of findings and the concordance between the nonclinical injection-site profile and the clinical safety experience (injection-site reactions as the principal drug-attributable finding, no dose-dependent systemic safety signal), support the continued clinical development of TILA-278 in moderate-to-severe UC.
2.6.6.10 Tables and Figures
Representative tabulations are provided in Section 2.6.7.
2.6.7 Toxicology Tabulated Summary
Table 2.6.7-1. Overview of the nonclinical toxicology program
| Study No. | Type | Species | Route / regimen | GLP | Key outcome |
|---|---|---|---|---|---|
| TILA278-TOX-001 | 4-week dose-range-finding | Cynomolgus | SC, weekly (0/30/100/200 mg/kg) | Yes | Well tolerated; NOAEL 200 mg/kg/week |
| TILA278-TOX-002 | 13-week repeat-dose + 8-week recovery (pivotal) | Cynomolgus | SC, weekly (0/10/30/100 mg/kg), 14 doses | Yes | Well tolerated; NOAEL 100 mg/kg/week; reversible findings |
| TILA278-TOX-003 | Tissue cross-reactivity | Human + cynomolgus tissues | In vitro IHC | Yes | Target-consistent binding; no off-target liability |
| TILA278-TOX-004 | ePPND | Cynomolgus | SC | Yes | In progress |
Table 2.6.7-2. Pivotal 13-week study (TILA278-TOX-002) — design and principal findings
| Element | Detail |
|---|---|
| Groups | Vehicle; 10, 30, 100 mg/kg/week SC |
| Animals | 5/sex/group main; +3/sex control & high dose (recovery) |
| Duration | 13 weeks (14 weekly doses) + 8-week recovery |
| Mortality | No test-article-related deaths |
| Clinical / body weight / food | No test-article-related effects |
| Safety pharmacology (CV/resp/CNS) | No test-article-related effects |
| Clinical pathology | Minimal, reversible ↑ acute-phase reactants (e.g., CRP) at high dose |
| Injection sites / local tolerance | Minimal-to-mild, reversible; no necrosis |
| Histopathology | Minimal, reversible epithelial hyperplasia (IL-22R pharmacology); no adverse findings |
| Immune parameters | No adverse immunotoxicity |
| Reversibility | Reversible/reversing by end of recovery |
| NOAEL | 100 mg/kg/week (highest dose) |
Table 2.6.7-3. Toxicokinetics summary — Study TILA278-TOX-002, Week 13 (sexes combined)
| Dose (mg/kg/week) | C_max (µg/mL) | AUC0–168h (µg·h/mL) | ADA incidence |
|---|---|---|---|
| 10 | 290 | 34,000 | Low-moderate |
| 30 | 880 | 105,000 | Low-moderate |
| 100 | 2,850 | 355,000 | Low |
Table 2.6.7-4. Exposure margins at the NOAEL (relative to high clinical dose, TILA278-201)
| Basis | NOAEL (cyno, 100 mg/kg/week) | Clinical high dose (projected steady state) | Margin |
|---|---|---|---|
| AUC (0–168 h) | 355,000 µg·h/mL | ~11,800 µg·h/mL | ~30× |
| C_max | 2,850 µg/mL | ~158 µg/mL | ~18× |
Projected clinical exposures are derived from the clinical pharmacology analyses presented in Module 2.7; margins are expressed relative to the high clinical dose evaluated in TILA278-201.
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