📚 Part of the TILA-278 Regulatory Dossier — Reader's Guide. This article shows the live document; edits to the source appear here automatically.

---

US IND — Application Summary (TILA-278)

Field	Value
Document ID	M1-IND
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	US FDA (IND)
Confidentiality	Confidential

Region-specific administrative document for the TILA-278 marketing application.

Change History

Version	Date	Author	Summary
1.0	2026-07-08	Regulatory Affairs	Initial issue

1. Introductory Statement and General Investigational Plan

1.1 Introductory Statement

Virtual Biopharma Inc. (hereafter "the Sponsor") submits this Investigational New Drug (IND) application to support the initiation of clinical development in the United States of TILA-278, a novel investigational biologic for the treatment of moderate-to-severe ulcerative colitis (UC).

TILA-278 is a recombinant humanized immunoglobulin G1 (IgG1) bispecific monoclonal antibody. The molecule combines two independent, mechanistically complementary binding activities in a single therapeutic entity:

• Anti-TL1A (TNFSF15) antagonist arm — neutralizes TL1A signaling, thereby dampening TH1/TH17-driven mucosal inflammation and attenuating the pro-fibrotic cascade that contributes to intestinal fibrosis in inflammatory bowel disease.
• IL-22 receptor (IL-22R) agonist arm — engages and activates IL-22R signaling on intestinal epithelial cells to promote epithelial regeneration, goblet-cell function, and restoration of the mucosal barrier.

The therapeutic hypothesis is that simultaneous suppression of the inflammatory drive (TL1A antagonism) and active promotion of mucosal healing (IL-22R agonism) will produce deeper and more durable disease control than agents acting on inflammation alone. This dual anti-inflammatory plus mucosal-restorative mechanism is directly aligned with the contemporary treatment goal in UC of combined clinical and endoscopic/mucosal remission.

TILA-278 is administered by subcutaneous (SC) injection. The drug product is presented as a sterile solution in a single-use prefilled syringe/autoinjector suitable for in-clinic and, ultimately, at-home administration.

Summary identification

Item	Description
Sponsor	Virtual Biopharma Inc.
Investigational product	TILA-278
Modality	Humanized IgG1 bispecific monoclonal antibody (anti-TL1A antagonist × IL-22R agonist)
Approximate molecular weight	~148 kDa
Route of administration	Subcutaneous (SC)
Proposed indication	Moderate-to-severe ulcerative colitis
Lead clinical protocol	TILA278-201
Application type	Original IND (US FDA)

1.2 Regulatory Status and Basis for the Submission

At the time of this submission, TILA-278 has completed a randomized, double-blind, placebo-controlled Phase 2b induction study (Protocol TILA278-201) conducted outside the United States. That study met its primary endpoint of clinical remission at Week 12 with a clear dose-ordered treatment effect and an acceptable safety profile (Section 5). No unexpected safety signal was identified, and the only consistently drug-attributable finding was injection-site reactions consistent with the SC route.

This IND is submitted to enable US clinical development of TILA-278, drawing on the completed TILA278-201 induction data as the principal body of previous human experience. The nonclinical package (Module 4) and the chemistry, manufacturing, and controls (CMC) package (Module 3) support administration of TILA-278 to human subjects at the exposures proposed for the planned US studies.

TILA-278 has not previously been the subject of a US IND. There have been no prior FDA regulatory actions (e.g., clinical holds) concerning this molecule.

1.3 General Investigational Plan (Coming 12 Months)

The Sponsor's overall development objective is to establish the efficacy and safety of TILA-278 for induction and maintenance of remission in adults with moderate-to-severe UC, and thereafter to evaluate the program in related inflammatory bowel disease indications.

Over the 12 months following IND clearance, the Sponsor plans to:

1. Confirm and extend the induction findings in a US/global population. Advance a confirmatory, adequately powered induction program in moderate-to-severe UC that reproduces the TILA278-201 primary endpoint (Week-12 clinical remission by modified Mayo score) in a population that includes US sites and both biologic-naïve and biologic-experienced patients.
2. Characterize maintenance therapy. Evaluate a maintenance dosing regimen following induction to establish durability of clinical remission, endoscopic improvement, and mucosal healing, and to define the long-term benefit–risk profile.
3. Complete the clinical pharmacology package. Characterize SC pharmacokinetics (PK) including bioavailability and dose proportionality, exposure–response for efficacy and safety, and immunogenicity (anti-drug antibody [ADA]) with its impact on PK, efficacy, and safety (Section 4).
4. Continue nonclinical characterization as required. Complete any chronic and reproductive/developmental toxicology in the cynomolgus monkey needed to support longer-duration dosing and broader populations, consistent with ICH S6(R1) (Section 3).

Estimated subject exposure in the coming year: approximately several hundred additional subjects across the planned induction and maintenance cohorts, at SC doses bracketing the TILA-278 Low and High dose levels evaluated in TILA278-201.

The number of subjects, dose levels, and duration described here represent the current plan and may be refined based on emerging data and regulatory feedback; material changes will be submitted as protocol amendments or information amendments to this IND.

---

2. Chemistry, Manufacturing, and Controls (CMC) Summary

This section summarizes the CMC information supporting the safe use of TILA-278 in the proposed clinical studies. Full details are provided in Module 3 (Quality); cross-references to specific Module 3 sections are given in Section 2.6.

2.1 Overview

TILA-278 drug substance (DS) is a recombinant humanized IgG1 bispecific monoclonal antibody expressed in a Chinese hamster ovary (CHO) cell line. The drug product (DP) is a sterile aqueous solution for SC administration presented in a single-use prefilled syringe/autoinjector. Manufacturing and control are conducted under current Good Manufacturing Practice (cGMP), and the control strategy is designed to assure identity, purity, potency, and safety appropriate to the phase of development.

2.2 Drug Substance

Attribute	Description
Type / structure	Recombinant humanized IgG1 bispecific mAb; two distinct antigen-binding specificities (anti-TL1A antagonist; IL-22R agonist) on an IgG1 framework
Expression system	CHO cell line, fed-batch cell culture
Capture / purification	Protein-A affinity capture followed by orthogonal polishing chromatography (e.g., cation- and anion-exchange)
Viral safety	Dedicated viral clearance steps (low-pH viral inactivation and viral-retentive nanofiltration) plus raw-material and cell-bank virus testing, per ICH Q5A
Formulated DS storage	≤ –40 °C

Characterization and control. The DS is characterized for:

• Identity — peptide mapping, intact and reduced mass by LC-MS, and confirmation of the bispecific pairing/assembly.
• Purity and product-related impurities — aggregates/high-molecular-weight species by SEC (≤ 2% aggregate), fragments/low-molecular-weight species by CE-SDS, and charge variants by imaged capillary isoelectric focusing (icIEF).
• Glycosylation — N-glycan profiling of the Fc glycans (e.g., afucosylation and high-mannose content) as a potential critical quality attribute.
• Potency / biological activity — a dual, arm-specific potency strategy comprising an anti-TL1A neutralization cell-based assay and an IL-22R agonism reporter/functional assay, each with defined acceptance criteria.
• Process- and safety-related impurities — host-cell protein, residual DNA, residual Protein A, and endotoxin/bioburden, each controlled to phase-appropriate limits.

2.3 Drug Product

Attribute	Description
Dosage form	Sterile solution for SC injection
Presentation	Single-use prefilled syringe / autoinjector
Nominal concentration	150 mg/mL
Formulation	Histidine/histidine-HCl buffer, pH ~5.8; polysorbate (e.g., polysorbate 80) as surfactant; stabilizing sugar (e.g., sucrose)
Container-closure	Type I glass syringe barrel with staked needle and elastomeric components qualified for biologics

The DP release specification includes appearance, protein concentration, pH, osmolality, sub-visible and visible particulates, purity/impurities (SEC, CE-SDS, icIEF), both potency assays, sterility, endotoxin, and container-closure/functional testing (e.g., extrusion/glide force, dose accuracy) appropriate to the device presentation.

2.4 Stability

Formal stability studies are ongoing under ICH Q1A/Q5C conditions (long-term, accelerated, and stress). Available data support the storage conditions and the in-use handling described in the protocol and Investigator's Brochure. The proposed DP shelf life is 24 months at 2–8 °C, protect from light, with defined in-use stability for room-temperature equilibration prior to injection.

2.5 Safety Assessment of the CMC Package

The manufacturing process, control strategy, viral-safety measures, and stability data are adequate to assure that clinical supplies of TILA-278 are of appropriate quality and safety for the proposed SC clinical use. No CMC issue has been identified that would place subjects at unreasonable risk. Manufacturing and analytical methods will continue to be developed and validated in step with clinical phase.

2.6 Cross-References to Module 3

Topic	Module 3 location
Drug substance – general information, manufacture, characterization, control, stability	3.2.S.1 – 3.2.S.7
Drug product – description, formulation, manufacture, control, container-closure, stability	3.2.P.1 – 3.2.P.8
Appendices – facilities, adventitious-agents (viral) safety	3.2.A.1 – 3.2.A.2
Regional quality information	3.2.R

---

3. Nonclinical Pharmacology and Toxicology Summary

This section summarizes the nonclinical program supporting first administration of TILA-278 in the proposed studies. Full study reports and tabulated data are in Module 4 (Nonclinical Study Reports); cross-references are given in Section 3.7. The program was designed in accordance with ICH S6(R1) for biotechnology-derived pharmaceuticals.

3.1 Species Selection and Relevance

TILA-278 binds human TL1A and human IL-22R with high specificity. Because both targets are engaged in a strictly human-specific manner, conventional rodent species are not pharmacologically relevant for repeat-dose toxicology. Consistent with ICH S6(R1), the nonclinical strategy therefore used:

• In vivo pharmacology in disease-relevant models employing a species-appropriate surrogate antibody and/or a target knock-in model to interrogate the intended dual mechanism; and
• Toxicology in the cynomolgus monkey, identified as a pharmacologically relevant species for both binding arms, for repeat-dose SC assessment.

3.2 Primary Pharmacodynamics

The intended dual mechanism was confirmed nonclinically:

• TL1A antagonism reduced TH1/TH17-associated cytokines and attenuated inflammatory and pro-fibrotic readouts in colitis/fibrosis models.
• IL-22R agonism enhanced epithelial regeneration and mucosal-barrier markers (e.g., regenerating-family and antimicrobial-peptide gene expression, epithelial restitution).
• The bispecific produced complementary anti-inflammatory and mucosal-healing effects consistent with the therapeutic hypothesis, with combined activity greater than that expected from inhibition of inflammation alone.

3.3 Secondary Pharmacology and Safety Pharmacology

Safety pharmacology endpoints were integrated into the repeat-dose cynomolgus toxicology studies per ICH S6(R1), with assessment of cardiovascular (including telemetry-based blood pressure, heart rate, and ECG intervals), respiratory, and central-nervous-system parameters. No adverse effects on vital-organ function were identified at the exposures tested.

3.4 Nonclinical Pharmacokinetics and Immunogenicity

Toxicokinetics in the cynomolgus monkey following SC administration were consistent with a monoclonal antibody exhibiting target-mediated drug disposition (TMDD) at low exposures and approximately linear kinetics at higher exposures, with a prolonged terminal half-life supporting infrequent SC dosing. Anti-drug antibodies were detected in a subset of animals, as is expected for a human antibody administered to a non-human species, without precluding sustained exposure over the dosing period. Tissue cross-reactivity studies using human and cynomolgus tissue panels showed binding consistent with the known distribution of the targets and no unexpected off-target binding.

3.5 Toxicology

The pivotal general-toxicology assessment comprised repeat-dose SC studies in the cynomolgus monkey of duration adequate to support the proposed clinical dosing. Key features:

Element	Summary
Species / route	Cynomolgus monkey; subcutaneous
Design	Repeat-dose, multiple dose levels with toxicokinetics and a recovery phase
Endpoints	Clinical signs, body weight, food consumption, clinical/anatomic pathology, immunophenotyping, local tolerance, safety-pharmacology parameters, toxicokinetics, ADA
Principal findings	No adverse target-organ toxicity; findings limited to expected exaggerated-pharmacology/immune-related changes and injection-site observations, reversible in recovery
NOAEL	Highest dose tested, providing multiples over anticipated clinical exposure

Local tolerance at the SC injection site was assessed within the repeat-dose studies and supports the clinical SC presentation.

3.6 Genotoxicity, Carcinogenicity, and Reproductive Toxicology

Consistent with ICH S6(R1), genotoxicity and carcinogenicity studies are not warranted for a monoclonal antibody of this class, and none were conducted. Reproductive and developmental toxicology is being addressed in a manner and timing appropriate to the intended population and dosing duration; the available package supports the proposed studies in a non-pregnant adult population with standard contraception requirements.

3.7 Integrated Nonclinical Safety Assessment and Cross-References to Module 4

The nonclinical pharmacology confirms the intended dual mechanism, and the cynomolgus toxicology program identifies no target-organ toxicity of concern at exposures exceeding those anticipated clinically, with an adequate safety margin to support the proposed SC doses. The overall nonclinical package supports the safe administration of TILA-278 in the planned clinical studies.

Topic	Module 4 location
Primary and secondary pharmacodynamics	4.2.1.1 – 4.2.1.2
Safety pharmacology	4.2.1.3
Nonclinical pharmacokinetics / toxicokinetics	4.2.2
Tissue cross-reactivity	4.2.3 (single-dose/general toxicity support)
Repeat-dose toxicology (cynomolgus, SC)	4.2.3.2
Local tolerance	4.2.3.6
Genotoxicity / carcinogenicity (justification for absence)	4.2.3.3 / 4.2.3.4

---

4. Clinical Pharmacology Summary

The clinical pharmacology of TILA-278 is characterized as that of a therapeutic IgG1 bispecific antibody administered subcutaneously:

• Absorption / bioavailability. SC administration is expected to give an absolute bioavailability in the range typical of therapeutic mAbs (approximately 60–70%), with delayed time-to-peak consistent with lymphatic absorption.
• Distribution and elimination. PK are dominated by target-mediated drug disposition (TMDD), yielding non-linear behavior at lower exposures and approximately linear elimination at higher exposures; the terminal half-life supports every-2-to-4-week SC dosing.
• Exposure–response. The dose-ordered efficacy observed in TILA278-201 (Section 5) supports a positive exposure–response relationship for clinical remission, which will be formalized in dedicated exposure–response analyses.
• Immunogenicity. ADA are assessed with a tiered assay strategy (screening → confirmatory → titer, with neutralizing-antibody characterization), and their impact on PK, efficacy, and safety is evaluated.
• Cardiac safety. Consistent with ICH E14/S7B for a large-molecule biologic with no expectation of direct ion-channel interaction, a dedicated thorough QT study is not warranted; cardiac safety is monitored via ECGs within the clinical program and the cynomolgus safety-pharmacology assessment.

Clinical pharmacokinetic and immunogenicity data from TILA278-201, together with the population PK and exposure–response analyses supporting the planned program, are provided in Module 5 (5.3.1–5.3.3).

---

5. Clinical Protocol Synopsis — Protocol TILA278-201

The full protocol is provided under Module 5 (5.3.5.1) and the corresponding regional protocol listing. The Investigator's Brochure summarizes the supporting nonclinical and clinical data. This completed induction study constitutes the principal previous human experience supporting the IND.

5.1 Synopsis

Field	Description
Protocol number	TILA278-201
Title	A Phase 2b, randomized, double-blind, placebo-controlled, parallel-group study of TILA-278 for induction of remission in moderate-to-severe ulcerative colitis
Phase	2b (induction)
Investigational product	TILA-278, administered subcutaneously at two dose levels (High and Low)
Comparator	Matching placebo, SC
Design	Randomized, double-blind, placebo-controlled, parallel-group
Treatment duration	12-week induction
Study visits	Weeks 0, 2, 4, 8, and 12
Randomization	1:1:1 (TILA-278 High: TILA-278 Low: Placebo)
Stratification	Baseline modified Mayo disease severity; prior biologic exposure
Screened / randomized	1700 screened; 900 randomized (High 299 / Low 300 / Placebo 301)

5.2 Objectives and Endpoints

• Primary objective: to evaluate the efficacy of TILA-278 versus placebo for induction of clinical remission at Week 12.
• Primary endpoint:clinical remission at Week 12, defined as a modified Mayo score ≤ 2 with no individual subscore > 1.
• Key secondary objectives: change from baseline in modified Mayo score; endoscopic improvement and mucosal healing; symptomatic response; and characterization of safety, tolerability, PK, and immunogenicity.

5.3 Population (Key Eligibility)

Eligible subjects were adults (≥ 18 years) with a diagnosis of UC established at least 3 months prior to screening and moderate-to-severe disease activity, defined by a baseline modified Mayo score in the moderate-to-severe range with a centrally read endoscopic subscore ≥ 2. Subjects were required to have demonstrated an inadequate response to, loss of response to, or intolerance of conventional therapy (corticosteroids and/or immunomodulators) and/or approved biologic or targeted synthetic agents. Key exclusions included Crohn's disease or indeterminate colitis, prior colectomy or planned colitis-related surgery, active or serious infection (including tuberculosis screening requirements), and other conditions that would confound assessment or increase participation risk. Enrollment was stratified by baseline modified Mayo severity and prior biologic exposure to promote balance across treatment arms.

5.4 Statistical Methods

The primary efficacy analysis compared each TILA-278 dose with placebo for Week-12 clinical remission in the Full Analysis Set (FAS). The LS-mean change from baseline in modified Mayo score was analyzed by ANCOVA with treatment and stratification factors and baseline score as covariate. Multiplicity across the two dose comparisons was controlled by a pre-specified testing procedure. Safety was summarized descriptively in the safety population.

5.5 Efficacy Results

Clinical remission at Week 12 (primary endpoint; FAS): a clear, dose-ordered treatment effect was observed, with both TILA-278 doses superior to placebo.

Arm	Remission, n/N	Remission rate
TILA-278 High	106/284	37.3%
TILA-278 Low	46/283	16.2%
Placebo	2/273	0.7%

Change from baseline in modified Mayo score at Week 12 (FAS; ANCOVA):

Arm	LS-mean change	Difference vs placebo (95% CI)	p-value
TILA-278 High	–3.36	–2.36 (–2.49, –2.23)	< 0.0001
TILA-278 Low	–2.76	–1.77 (–1.90, –1.64)	< 0.0001
Placebo	–1.00	—	—

Both dose comparisons were highly statistically significant, and the magnitude of effect and remission rates were dose-ordered (High > Low > Placebo), supporting a positive exposure–response relationship consistent with the intended dual mechanism.

5.6 Safety Results

TILA-278 was generally well tolerated over the 12-week induction period. There was no dose-dependent safety signal; the principal drug-attributable finding was injection-site reactions, higher on active SC drug as expected for the SC route.

Parameter (subjects)	TILA-278 High	TILA-278 Low	Placebo
≥ 1 TEAE	109	131	130
Serious adverse events (SAEs)	3	0	4
Deaths	2	0	1
Discontinuations	17	17	29

• Deaths (2 High / 0 Low / 1 Placebo) were all assessed as unrelated to study drug.
• Discontinuations were highest on placebo (29), driven predominantly by lack of efficacy.
• Most frequent adverse events across the study included nasopharyngitis, headache, worsening UC (higher on placebo), anaemia, arthralgia, upper respiratory tract infection, injection-site reaction (higher on active SC drug), and nausea.

5.7 Conclusions from TILA278-201

TILA278-201 met its primary endpoint, demonstrating statistically significant and clinically meaningful, dose-ordered induction of clinical remission with TILA-278 versus placebo in moderate-to-severe UC, together with a favorable and manageable safety profile in which injection-site reactions were the main drug-attributable finding and no dose-dependent safety signal was observed. These results provide a strong clinical basis for the proposed US development program described in the General Investigational Plan (Section 1.3).

---

6. Cross-Reference Index (CTD Modules)

Content	CTD module / location
Introductory statement and general investigational plan	Module 1 (this summary); Form FDA 1571
Quality (CMC)	Module 3 (3.2.S, 3.2.P, 3.2.A, 3.2.R)
Nonclinical study reports	Module 4 (4.2.1 – 4.2.3)
Clinical pharmacology and study data	Module 5 (5.3.1 – 5.3.3)
Clinical protocol TILA278-201	Module 5 (5.3.5.1)
Investigator's Brochure	Module 1 / Module 5 supportive