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Module 1 (KR) — Administrative & Label (TILA-278)

Document ID: M1-KR
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): MFDS

Korea (MFDS) Administrative & Label — TILA-278

This module contains the Ministry of Food and Drug Safety (MFDS) regional administrative content and the Korean Product Information for TILA-278, a recombinant humanized bispecific monoclonal antibody that combines TL1A (TNFSF15) antagonism with interleukin-22 receptor (IL-22R) agonism in a single IgG1 molecule. The active substance is expressed in a Chinese hamster ovary (CHO) cell culture system, purified by Protein A affinity capture followed by orthogonal polishing chromatography, and formulated as a solution for subcutaneous injection. The applicant/marketing authorization holder is Virtual Biopharma Inc.

The label is written to the MFDS Korean Product Information format and is maintained in strict consistency with the clinical, nonclinical, and quality data presented elsewhere in the dossier. The marketing authorization application is compiled in the ICH M4 Common Technical Document structure; the administrative particulars, indication statement, and posology in this module are cross-referenced to the Module 2 summaries and to the primary study reports in Module 5. The corresponding foreign filing for the same product is a Biologics License Application submitted under 21 CFR Part 601. Quality and nonclinical development follow the biotechnology-specific ICH guidance applicable to this modality — ICH Q5A(R2) (viral safety of biotechnology products derived from cell lines of human or animal origin), Q5C (stability testing of biotechnological/biological products), Q6B (specifications and analytical procedures for biotechnological products), and S6(R1) (preclinical safety evaluation of biotechnology-derived pharmaceuticals). Clinical conduct followed the principles of ICH E6 Good Clinical Practice, and the statistical analyses followed ICH E9.

Indications

TILA-278 is indicated for the treatment of moderate-to-severe active Ulcerative Colitis in adult patients who have had an inadequate response, loss of response, or intolerance to conventional therapy (aminosalicylates, corticosteroids, or immunomodulators) or to a biologic or targeted synthetic agent.

The therapeutic rationale rests on a dual, complementary mechanism engaged by a single bispecific molecule. The anti-TL1A arm acts as an antagonist: by neutralizing TL1A (TNFSF15) and blocking its engagement of death receptor 3 (DR3), it dampens the Th1/Th17 and innate lymphoid cell–driven inflammatory signaling that sustains mucosal injury, and it attenuates the pro-fibrotic signaling implicated in intestinal tissue remodeling. The IL-22R arm acts as an agonist: by engaging IL-22RA1 on intestinal epithelial cells and activating downstream STAT3 signaling, it promotes epithelial regeneration, mucin and antimicrobial peptide production, and restoration of the mucosal barrier. In combination, the molecule is designed to suppress the inflammatory and fibrotic drivers of disease while actively supporting epithelial and mucosal healing. The induction indication is supported by the Phase 2b study TILA278-201; posology beyond the 12-week induction period is to be established by the ongoing program.

Clinical efficacy (TILA278-201)

TILA278-201 was a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group induction study evaluating two subcutaneous dose regimens of TILA-278 against placebo in adults with moderate-to-severe active Ulcerative Colitis. Participants were randomized 1:1:1 to a high-dose regimen (TILA-278 High), a low-dose regimen (TILA-278 Low), or placebo, and treated over a 12-week induction period with the primary assessment at Week 12. Of 1700 patients screened, 900 were randomized (299 High / 300 Low / 301 Placebo). The Full Analysis Set comprised 840 patients (284 High / 283 Low / 273 Placebo). Disease activity was measured with the modified Mayo score, comprising stool frequency, rectal bleeding, and centrally read endoscopy subscores.

The primary endpoint was clinical remission at Week 12, defined as a modified Mayo score of 2 or lower with no individual subscore greater than 1. Both active regimens were statistically superior to placebo: clinical remission was achieved by 37.3% (106/284) of the high-dose group, 16.2% (46/283) of the low-dose group, and 0.7% (2/273) of the placebo group. The binary remission endpoint was analyzed on the Full Analysis Set with non-responder imputation for missing data; the continuous modified Mayo change endpoint was analyzed by a mixed model for repeated measures on the randomized population. Multiplicity across the primary and key secondary endpoints was controlled by a pre-specified hierarchical testing procedure.

Arm	N	LS-mean Δ Modified Mayo Score @ Wk 12 (points)	Diff vs placebo (95% CI)	p
TILA-278 High	299	-3.36	-2.36 (-2.49, -2.23)	0.0000
TILA-278 Low	300	-2.76	-1.77 (-1.90, -1.64)	0.0000
Placebo	301	-1.00	— (reference)	—

Responder analysis — Clinical remission (Mayo <= 2)

Arm	N	Responders, n/N	Rate	Risk diff vs placebo (95% CI, %)	p
TILA-278 High	284	106/284	37.3%	36.6% (30.9, 42.3)	0.0000
TILA-278 Low	283	46/283	16.2%	15.5% (11.1, 19.9)	0.0000
Placebo	273	2/273	0.7%	— (reference)	—

A dose-ordered response was observed on both the continuous and the binary remission endpoints, consistent with the intended pharmacology. The key secondary endpoint of endoscopic improvement, defined as a Mayo endoscopic subscore of 1 or lower at Week 12 by central reading, reinforced the primary finding, with both active regimens separating clearly from placebo.

Key secondary endpoint — Endoscopic improvement (Mayo endoscopic subscore <= 1) @ Wk 12

Arm	N	Endoscopic improvement
TILA-278 High	284	48.9%
TILA-278 Low	283	27.9%
Placebo	273	6.2%

The pattern across clinical remission, modified Mayo score reduction, and endoscopic improvement is internally consistent and coherent with the dual mechanism: suppression of inflammatory and fibrotic drivers together with active support of epithelial and mucosal healing.

Dosage & Administration

TILA-278 is administered by subcutaneous injection. In TILA278-201 two dose regimens (a high-dose and a low-dose regimen) were evaluated over the 12-week induction period; the induction posology to be carried forward and any subsequent maintenance regimen are to be finalized on the totality of the program. Administration is by, or under the supervision of, a healthcare professional trained in subcutaneous injection technique. Each presentation is intended for single use. Before administration the product should be allowed to reach room temperature and inspected visually; it should not be used if particulate matter or discoloration is present. No dose adjustment on the basis of renal or hepatic function is anticipated for a monoclonal antibody eliminated by catabolism rather than by renal or hepatic metabolic clearance.

Contraindications

TILA-278 is contraindicated in patients with known hypersensitivity to the active substance or to any of the excipients, and in patients with clinically important active infection, including active tuberculosis, until the infection is controlled.

Warnings & Precautions

• Infections. Because the molecule modulates immune and mucosal pathways, patients should be evaluated for active and latent infection, including tuberculosis, before initiation and monitored during treatment. Treatment should not be started in the presence of a clinically important active infection and should be interrupted if a serious infection develops.
• Tuberculosis. Patients should be screened for latent tuberculosis before starting therapy and managed according to local guidance.
• Hypersensitivity and injection reactions. Hypersensitivity reactions and injection-site reactions may occur; patients should be observed and managed appropriately, and treatment discontinued if a serious hypersensitivity reaction occurs.
• Immunizations. Live vaccines should be avoided during treatment; it is recommended that patients be brought up to date with immunizations before initiation.
• Immunogenicity. As with all therapeutic proteins, anti-drug antibodies may develop and could affect exposure or response; persistent loss of response should prompt clinical reassessment.

Adverse Reactions

The safety profile in the 12-week induction study was consistent with that expected for a subcutaneously administered immunomodulatory monoclonal antibody in this population. The most commonly reported events included injection-site reactions, nasopharyngitis and other upper respiratory events, and headache. Infections were monitored as an event of interest given the mechanism. The complete tabulated safety data, including serious adverse events and events of special interest, are presented in the Module 5 study report and summarized in the Module 2 clinical safety summary.

Immunogenicity

Immunogenicity was assessed using a tiered, validated assay strategy (screening, confirmatory, and titer determination), with characterization of neutralizing anti-drug antibodies and evaluation of the relationship between anti-drug antibody status and pharmacokinetics, efficacy, and safety. Immunogenicity results are interpreted in the context of assay sensitivity and drug tolerance, in line with current bioanalytical expectations for therapeutic proteins.

Use in Specific Populations

• Pregnancy. As a humanized IgG1 antibody, the molecule is expected to cross the placenta increasingly during the second and third trimesters; use in pregnancy should follow a benefit–risk assessment. Reproductive findings, where available, derive from the pharmacologically relevant nonclinical species.
• Lactation. Human immunoglobulin G is present in breast milk; a decision on use during lactation should weigh the benefit of treatment to the mother against potential effects on the infant.
• Pediatric use. Safety and efficacy in pediatric patients have not been established.
• Geriatric use. No specific dose adjustment is proposed for older patients; infection risk in this population warrants the general precautions above.
• Renal or hepatic impairment. No dose adjustment is anticipated, as elimination proceeds by catabolic degradation to amino acids rather than by renal or hepatic clearance.

Clinical Pharmacology

TILA-278 exhibits pharmacokinetics characteristic of a bispecific IgG1 antibody against membrane- and soluble-target systems, with target-mediated drug disposition (TMDD) contributing nonlinearity at lower concentrations and approximately linear disposition once target-mediated pathways are saturated. Following subcutaneous administration the antibody is absorbed via the lymphatics and cleared predominantly through proteolytic catabolism to peptides and amino acids, with FcRn-mediated recycling supporting an elimination profile typical of an IgG1. The molecule is not a substrate for cytochrome P450 enzymes and is not renally eliminated, and it has low potential for classical small-molecule drug–drug interactions; the only theoretical interaction pathway relevant to this class is modulation of cytokine-regulated CYP expression during resolution of inflammation. Exposure–response relationships and the influence of anti-drug antibodies on exposure are described in the Module 2 clinical pharmacology summary.

Nonclinical Safety

The nonclinical program was designed in accordance with ICH S6(R1) for biotechnology-derived pharmaceuticals. The cynomolgus monkey was the sole pharmacologically relevant species, established by demonstrated binding and functional cross-reactivity of both the TL1A-antagonist and IL-22R-agonist arms in that species; rodents were not pharmacologically relevant. Repeat-dose toxicity was therefore evaluated by the subcutaneous route in cynomolgus monkeys, with safety pharmacology endpoints (cardiovascular, respiratory, and central nervous system observations) incorporated into the repeat-dose design, together with toxicokinetics, immunogenicity assessment, and tissue cross-reactivity evaluation. Consistent with ICH S6(R1) for a monoclonal antibody, standalone genotoxicity and carcinogenicity studies were not conducted, and dedicated hERG and thorough-QT studies were not warranted for this modality; cardiac electrophysiology risk was addressed within the in vivo safety pharmacology assessments in the relevant species.

Quality (CMC) Summary

The active substance is a recombinant humanized anti-TL1A × IL-22R bispecific IgG1 monoclonal antibody produced by fed-batch culture of a CHO cell line, with a two-tiered cell bank system (master and working cell banks) characterized in line with ICH Q5A(R2) and Q5D. Downstream processing comprises Protein A affinity capture followed by orthogonal polishing chromatography, with dedicated viral safety steps (low-pH inactivation and viral filtration, with demonstrated viral clearance) as required by ICH Q5A(R2). The specification is established per ICH Q6B and covers identity, purity and impurities (size variants by SEC for aggregates and CE-SDS for fragments and half-antibody species; charge variants by imaged capillary isoelectric focusing), the N-glycan profile, host cell protein, residual host cell DNA, and endotoxin, together with control of correct chain pairing and mispaired species inherent to the bispecific format. Potency is assessed by dual functional bioassays that reflect both mechanisms of the molecule — TL1A binding and neutralization for the antagonist arm and IL-22R binding and agonist activity for the agonist arm — so that the simultaneous bifunctionality of the product is controlled. Stability is established under ICH Q5C to support the proposed shelf life and in-use conditions, and any manufacturing changes are supported by comparability in line with ICH Q5E.

Storage & Handling

Store refrigerated at 2–8 °C in the original carton to protect from light. Do not freeze and do not shake. Do not use if the product has been frozen. Allow the product to reach room temperature before administration and administer promptly after removal from refrigeration. For single use only; discard any unused portion.

Administrative Particulars

• Applicant / Marketing Authorization Holder: Virtual Biopharma Inc.
• Product name: TILA-278
• Active substance: recombinant humanized anti-TL1A × IL-22R bispecific monoclonal antibody (IgG1), CHO-derived
• Pharmaceutical form: solution for subcutaneous injection
• Pharmacotherapeutic group: selective immunomodulator acting on the TNF-superfamily (TL1A) and interleukin-22 receptor pathways
• Regulatory context: MFDS marketing authorization application compiled in ICH M4 CTD format; the corresponding foreign filing is a Biologics License Application under 21 CFR Part 601
• Cross-references: Administrative content, indication, and posology in this module are consistent with the Module 2 summaries, the Module 3 quality documentation, and the Module 5 clinical study reports for TILA278-201.