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

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Module 1 (US) — Administrative & Draft US Prescribing Information (TILA-278)

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

Module 1 (US) — Administrative Information and Prescribing Information

Application type: Original Biologics License Application (BLA), submitted under Section 351(a) of the Public Health Service Act (PHS Act) and 21 CFR 601.2 Proposed product: TILA-278 (proposed proprietary name TILVARA; proposed nonproprietary name tilazumig) injection, for subcutaneous use Applicant/Sponsor: Virtual Biopharma Inc. Cross-reference IND: IND 1XXXXX BLA number: BLA 761XXX Proposed indication: Induction of clinical remission in adults with moderately to severely active ulcerative colitis (UC) eCTD sequence: 0000 (original submission)

This Module 1 is region-specific to the United States and is organized in accordance with the FDA Comprehensive Table of Contents Headings and Hierarchy for eCTD Module 1 and the guidance Providing Regulatory Submissions in Electronic Format — Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications. The scientific evidence supporting the proposed indication is provided in Modules 2–5; the pivotal evidence of effectiveness is Study TILA278-201 (Protocol TILA278-201), a Phase 2b randomized, double-blind, placebo-controlled 12-week induction study.

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1.1 Forms

eCTD node	Form	Content	Status
1.1	FDA Form 356h	Application to Market a New or Abbreviated New Drug or Biologic for Human Use — executed by the responsible official of Virtual Biopharma Inc.	Signed
1.1	FDA Form 3674	Certification of Compliance with ClinicalTrials.gov (NCT) requirements (42 USC 282(j))	Signed
1.1	FDA Form 3397	User Fee Cover Sheet (PDUFA program fee for an original BLA requiring clinical data)	Attached

Form 356h identifies the establishment(s) responsible for drug substance and drug product manufacture, testing, packaging, and labeling; the corresponding facility information is provided in Module 3.2.A.1 and cross-referenced in Section 1.3.1 below.

1.2 Cover Letter

The cover letter (eCTD 1.2) transmits the original BLA and states the following:

• Purpose: Original BLA under 351(a) of the PHS Act seeking licensure of TILA-278 for the induction of clinical remission in adults with moderately to severely active UC.
• Regulatory pathway and designations: The submission relies on the pivotal induction study TILA278-201. Fast Track designation was granted; the applicant requests Priority Review under the PDUFA VII performance goals on the basis of a therapy that, if approved, would provide a mechanistically distinct treatment option (dual TL1A antagonism / IL-22 receptor agonism) for a serious disease.
• Pre-submission history: Content and format were aligned with the Agency at the End-of-Phase-2 (Type B) meeting held (see Section 1.6).
• Contents: A complete eCTD submission (Modules 1–5), including the draft Prescribing Information at Section 1.14.1.3, the annotated draft labeling at 1.14.1.2, and draft container/carton labeling at 1.14.1.1.
• Point of contact: The U.S. regulatory agent named in Section 1.3.

1.3 Administrative Information

1.3.1 Applicant / Contact / Agent

Item	Detail
Applicant (BLA holder)	Virtual Biopharma Inc.
Authorized U.S. agent / Regulatory contact	[Name], VP Regulatory Affairs, Virtual Biopharma Inc.
Establishment registration	Drug substance and drug product facilities registered under 21 CFR Part 207; FEI numbers provided in Module 3.2.A.1

1.3.3 Debarment Certification (Section 306(k)(1) of the FD&C Act) — The applicant certifies that it did not and will not use in any capacity the services of any person debarred under Section 306.

1.3.4 Financial Certification and Disclosure (21 CFR Part 54) — FDA Form 3454 (certification) is provided for clinical investigators in Study TILA278-201; no disclosable financial interests requiring Form 3455 were identified.

1.3.5 Patent Information / 1.3.7 Exclusivity Claim — As a biological product licensed under 351(a) of the PHS Act, TILA-278 is not subject to Orange Book patent listing. Reference-product exclusivity under Section 351(k)(7) of the PHS Act (12 years from the date of first licensure) is anticipated upon approval.

1.4 References / Cross-References

No letters of authorization to a Drug Master File are relied upon for the drug substance. Any excipient or container-closure DMF authorizations are listed in Module 3.2 and cross-referenced here.

1.5 Application Status / Regulatory History

Milestone	Reference	Date
IND opened (allowed to proceed)	IND 1XXXXX
Fast Track designation granted
End-of-Phase-2 (Type B) meeting	See 1.6
Pivotal induction study TILA278-201 completed	CSR in Module 5.3.5.1
Original BLA submitted (this sequence)	BLA 761XXX

The substantial evidence of effectiveness for the proposed induction indication derives from Study TILA278-201. A maintenance study, TILA278-301, is ongoing; the applicant will submit maintenance efficacy and long-term safety as a supplement and, as applicable, under postmarketing commitments/requirements agreed with the Agency.

1.6 Meetings

The End-of-Phase-2 (Type B) meeting minutes (eCTD 1.6.3) record Agency agreement on: the primary endpoint (clinical remission by modified Mayo score at Week 12); the acceptability of the modified Mayo definition of remission; the safety database size adequate to characterize the induction safety profile; and the content of the proposed label, including the framing of the indication as induction of clinical remission. Points requiring further data (durability of response and maintenance dosing) are addressed by the ongoing maintenance program.

1.9 Pediatric Administrative Information (PREA / iPSP)

An Initial Pediatric Study Plan (iPSP) was submitted under Section 505B of the FD&C Act as applied to biologics. UC in the pediatric population (ages 5 to <18 years) is a serious disease relevant to this product; the applicant proposes a deferral of pediatric studies until adult effectiveness and safety are established, with a proposed pediatric development plan and, where justified, a partial waiver for children <5 years (in whom moderately-to-severely active UC is rare).

1.12 / 1.13 Other Correspondence; Annual Reports

Not applicable to this original submission beyond items referenced above.

1.14 Labeling

• 1.14.1.1 Draft container and carton labeling (single-dose prefilled syringe and single-dose prefilled autoinjector) — provided.
• 1.14.1.2 Annotated draft Prescribing Information cross-referencing the supporting data in Modules 2–5 — provided.
• 1.14.1.3 Draft Prescribing Information (Physician Labeling Rule format, 21 CFR 201.56/201.57) — reproduced in full below.

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1.14.1.3 — Draft United States Prescribing Information (USPI)

DRAFT LABELING. The following draft Prescribing Information is submitted for Agency review. Bracketed items denote information to be finalized in the approved labeling — including the final commercial presentation, the initial approval and revision dates, NDC and U.S. license numbers, and the quality and clinical-pharmacology parameters confirmed in Modules 3 and 5. Section numbering follows 21 CFR 201.56(d)(1) (Physician Labeling Rule). Sections omitted from the full prescribing information (e.g., 9 and 15) are reserved in accordance with 21 CFR 201.56(d)(2) because none of their content applies.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use TILA-278 safely and effectively. See full prescribing information for TILA-278.TILA-278 (tilazumig) injection, for subcutaneous useInitial U.S. Approval:

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INDICATIONS AND USAGE (1) TILA-278 is a tumor necrosis factor–like ligand 1A (TL1A) antagonist and interleukin-22 (IL-22) receptor agonist bispecific antibody indicated for the induction of clinical remission in adult patients with moderately to severely active ulcerative colitis (UC). (1)

DOSAGE AND ADMINISTRATION (2)

• Prior to initiation, evaluate for tuberculosis (TB) infection, screen for hepatitis B virus (HBV), and complete age-appropriate immunizations. (2.1, 5.1, 5.4)
• Recommended induction dosage: 450 mg by subcutaneous (SC) injection at Weeks 0, 2, 4, and 8. Evaluate clinical response at Week 12. (2.2)
• Discontinue in patients who show no evidence of therapeutic benefit by Week 12. (2.2)
• For SC injection into the abdomen, thigh, or upper arm; rotate injection sites. May be self-administered after training. (2.3)

DOSAGE FORMS AND STRENGTHS (3) Injection: 450 mg/3 mL (150 mg/mL) solution in a single-dose prefilled syringe or single-dose prefilled autoinjector. (3)

CONTRAINDICATIONS (4) Known serious hypersensitivity to tilazumig or to any excipient. (4)

WARNINGS AND PRECAUTIONS (5)

• Infections: May increase the risk of infections. Do not initiate during a clinically important active infection. Evaluate for TB before and during therapy. (5.1)
• Hypersensitivity and immunogenicity: Hypersensitivity reactions may occur; anti-drug antibodies (ADA) were detected. Discontinue for serious hypersensitivity. (5.2)
• Injection-site reactions: The most common drug-attributable adverse reaction; usually mild-to-moderate and self-limited. (5.3)
• Immunizations: Avoid live vaccines during treatment. (5.4)

ADVERSE REACTIONS (6) Most common adverse reactions (≥3% and greater than placebo) were nasopharyngitis, injection-site reactions, headache, upper respiratory tract infection, arthralgia, and nausea. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Virtual Biopharma Inc. at 1-8XX-XXX-XXXX or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS (8)

• Pregnancy: Available data are insufficient to establish a drug-associated risk; monoclonal IgG1 antibodies are actively transported across the placenta in the second and third trimesters. (8.1)
• Lactation: No data on presence in human milk or effects on the breastfed infant. (8.2)

See 17 for PATIENT COUNSELING INFORMATION.Revised:

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FULL PRESCRIBING INFORMATION: CONTENTS*

1. INDICATIONS AND USAGE
2. DOSAGE AND ADMINISTRATION

• 2.1 Testing and Assessments Prior to Initiation
• 2.2 Recommended Dosage
• 2.3 Preparation and Administration
• 2.4 Missed Dose

3. DOSAGE FORMS AND STRENGTHS
4. CONTRAINDICATIONS
5. WARNINGS AND PRECAUTIONS

• 5.1 Infections
• 5.2 Hypersensitivity Reactions and Immunogenicity
• 5.3 Injection-Site Reactions
• 5.4 Immunizations
• 5.5 Malignancy

6. ADVERSE REACTIONS

• 6.1 Clinical Trials Experience
• 6.2 Immunogenicity

7. DRUG INTERACTIONS
8. USE IN SPECIFIC POPULATIONS

• 8.1 Pregnancy
• 8.2 Lactation
• 8.3 Females and Males of Reproductive Potential
• 8.4 Pediatric Use
• 8.5 Geriatric Use
• 8.6 Renal and Hepatic Impairment

10. OVERDOSAGE
11. DESCRIPTION
12. CLINICAL PHARMACOLOGY

• 12.1 Mechanism of Action
• 12.2 Pharmacodynamics
• 12.3 Pharmacokinetics

13. NONCLINICAL TOXICOLOGY

• 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14. CLINICAL STUDIES
15. HOW SUPPLIED/STORAGE AND HANDLING
16. PATIENT COUNSELING INFORMATION

*Sections or subsections omitted from the full prescribing information are not listed.

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FULL PRESCRIBING INFORMATION

1. INDICATIONS AND USAGE

TILA-278 is indicated for the induction of clinical remission in adult patients with moderately to severely active ulcerative colitis (UC).

2. DOSAGE AND ADMINISTRATION

2.1 Testing and Assessments Prior to Initiation

Prior to initiating TILA-278:

• Evaluate patients for tuberculosis (TB) infection with a TB risk assessment and a TB test. Do not administer TILA-278 to patients with active TB. Initiate treatment of latent TB prior to administering TILA-278 [see Warnings and Precautions (5.1)].
• Screen for hepatitis B virus (HBV) infection [see Warnings and Precautions (5.1)].
• Complete all age-appropriate immunizations according to current immunization guidelines [see Warnings and Precautions (5.4)].

2.2 Recommended Dosage

The recommended induction dosage of TILA-278 is 450 mg administered by subcutaneous injection at Weeks 0, 2, 4, and 8.

Evaluate clinical response at Week 12. Discontinue TILA-278 in patients who do not show evidence of therapeutic benefit by Week 12 [see Clinical Studies (14)]. Continued treatment beyond the induction period should be guided by maintenance data when available.

2.3 Preparation and Administration

TILA-278 is intended for use under the guidance and supervision of a healthcare provider. After proper training in subcutaneous injection technique, a patient may self-inject or a caregiver may administer TILA-278 if a healthcare provider determines it is appropriate.

• Before use, allow the prefilled syringe or autoinjector to reach room temperature for approximately 30 minutes; do not warm by any other method and do not remove the needle cap during this time.
• Inspect visually; the solution is a clear to slightly opalescent, colorless to pale yellow solution. Do not use if the solution is cloudy, discolored, or contains particulate matter, or if the device is damaged.
• Inject into the abdomen (avoiding the 2-inch area around the navel), the front of the thigh, or the outer upper arm (caregiver administration only). Rotate injection sites. Do not inject into areas where the skin is tender, bruised, red, hard, or affected by psoriasis, scars, or stretch marks.
• Each prefilled syringe/autoinjector is for single use only.

2.4 Missed Dose

If a dose is missed, administer the dose as soon as possible; thereafter, resume dosing at the regularly scheduled interval.

3. DOSAGE FORMS AND STRENGTHS

Injection: 450 mg/3 mL (150 mg/mL) as a clear to slightly opalescent, colorless to pale yellow solution supplied in:

• a single-dose prefilled syringe, and
• a single-dose prefilled autoinjector.

4. CONTRAINDICATIONS

TILA-278 is contraindicated in patients with a history of serious hypersensitivity reaction to tilazumig or to any of the excipients [see Warnings and Precautions (5.2), Description (11)].

5. WARNINGS AND PRECAUTIONS

5.1 Infections

TILA-278 may increase the risk of infections through modulation of TL1A-dependent TH1/TH17 immune responses [see Clinical Pharmacology (12.1)]. In the pivotal induction study, the most frequently reported infections included nasopharyngitis and upper respiratory tract infection, generally at rates similar to placebo [see Adverse Reactions (6.1)].

• Do not initiate TILA-278 in patients with a clinically important active infection until the infection resolves or is adequately treated.
• Consider the risks and benefits before initiating TILA-278 in patients with chronic or recurrent infection.
• Instruct patients to seek medical advice if signs or symptoms of infection occur. If a patient develops a serious infection, discontinue TILA-278 until the infection resolves.
• Tuberculosis: Evaluate for latent and active TB before and during treatment. Do not administer to patients with active TB.
• Hepatitis B: Screen for HBV before initiating. Monitor HBV carriers during and for several months following therapy; if reactivation occurs, discontinue TILA-278 and initiate appropriate treatment.

5.2 Hypersensitivity Reactions and Immunogenicity

Hypersensitivity reactions may occur. As with all therapeutic proteins, TILA-278 is immunogenic; anti-drug antibodies were detected in treated patients [see Adverse Reactions (6.2)]. If a serious hypersensitivity reaction occurs, discontinue TILA-278 immediately and institute appropriate therapy.

5.3 Injection-Site Reactions

Injection-site reactions were the most frequent drug-attributable adverse reaction and occurred more frequently in patients receiving TILA-278 than placebo [see Adverse Reactions (6.1)]. Reactions (including injection-site erythema, pain, pruritus, and swelling) were generally mild to moderate in severity, self-limited, and did not typically require discontinuation. Rotating injection sites may reduce the likelihood of reactions [see Dosage and Administration (2.3)].

5.4 Immunizations

Prior to initiating TILA-278, complete all age-appropriate immunizations according to current immunization guidelines. Avoid the use of live vaccines during treatment with TILA-278. No data are available on the secondary transmission of infection by live vaccines in patients receiving TILA-278.

5.5 Malignancy

The impact of long-term treatment with an immunomodulatory antibody on the risk of malignancy is not known. Because the IL-22 receptor–agonist activity of TILA-278 promotes intestinal epithelial proliferation, and because immunomodulation may alter tumor immune surveillance, a theoretical potential to influence malignancy risk cannot be excluded [see Clinical Pharmacology (12.1)]. Malignancies were not identified as a safety signal in the 12-week induction study; the study duration and size do not permit assessment of long-term malignancy risk [see Adverse Reactions (6.1)].

6. ADVERSE REACTIONS

The following clinically significant adverse reactions are described elsewhere in the labeling:

• Infections [see Warnings and Precautions (5.1)]
• Hypersensitivity Reactions and Immunogenicity [see Warnings and Precautions (5.2)]
• Injection-Site Reactions [see Warnings and Precautions (5.3)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of TILA-278 was evaluated in Study TILA278-201, a 12-week, randomized, double-blind, placebo-controlled induction study in adults with moderately to severely active UC. A total of 900 patients were randomized 1:1:1 to TILA-278 High (450 mg; n=299), TILA-278 Low (150 mg; n=300), or placebo (n=301). The safety analysis set comprised all patients who received at least one dose of study drug [see Clinical Studies (14)].

Table 1. Overview of Adverse Events During the 12-Week Induction Period (Safety Analysis Set)

Event category	TILA-278 High (N=299)	TILA-278 Low (N=300)	Placebo (N=301)
≥1 treatment-emergent adverse event (TEAE), n	109	131	130
Serious adverse events (SAE), n	3	0	4
Deaths, n	2	0	1
Discontinuations due to adverse events, n	17	17	29

All deaths were assessed by the investigator as unrelated to study drug. Discontinuations in the placebo group were driven predominantly by lack of efficacy (worsening UC) rather than by drug toxicity. No dose-dependent safety signal was identified across the TILA-278 High and Low groups.

Adverse reactions reported in ≥3% of patients in either TILA-278 group during the 12-week induction period are presented in Table 2.

Table 2. Adverse Reactions Reported in ≥3% of Patients in Either TILA-278 Group (Study TILA278-201, Safety Analysis Set)

Adverse reaction	TILA-278 High (N=299)	TILA-278 Low (N=300)	Placebo (N=301)
Nasopharyngitis	7.4%	6.7%	6.0%
Injection-site reaction*	8.4%	7.0%	2.3%
Headache	5.4%	5.0%	4.7%
Upper respiratory tract infection	4.3%	4.7%	3.7%
Arthralgia	3.7%	3.3%	3.0%
Nausea	3.0%	2.7%	2.3%
Anaemia	3.0%	3.3%	4.3%

*Injection-site reaction is a grouped term including injection-site erythema, pain, pruritus, and swelling, and was the principal drug-attributable finding [see Warnings and Precautions (5.3)].

Worsening of ulcerative colitis was reported more frequently in the placebo group than in either TILA-278 group and is attributable to the underlying disease; it is not tabulated above as a drug-related adverse reaction.

6.2 Immunogenicity

As with all therapeutic proteins, there is potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to tilazumig with the incidence of antibodies to other products may be misleading.

Immunogenicity was assessed using a validated tiered assay format (screening, confirmatory, and titer, with a separate neutralizing-antibody assay) [see Clinical Pharmacology (12.3)]. In Study TILA278-201, treatment-emergent anti-drug antibodies were detected in 7.9% of TILA-278–treated patients over the 12-week induction period, of whom 26.6% had neutralizing antibodies. No clinically meaningful impact of ADA on the pharmacokinetics, clinical remission rate, or overall safety of TILA-278 was observed over the induction period; ADA positivity showed a modest association with injection-site reactions.

7. DRUG INTERACTIONS

No formal drug-interaction studies have been conducted with TILA-278. As a monoclonal antibody, TILA-278 is not eliminated by cytochrome P450 (CYP) enzymes and is not expected to have direct effects on CYP enzymes or transporters. During chronic inflammation, elevated levels of certain cytokines can suppress CYP enzyme activity; the effect of TILA-278–mediated modulation of inflammation on CYP substrate exposure has not been established. Monitor patients receiving concomitant CYP substrates with a narrow therapeutic index for effect or drug concentration as clinically indicated.

Avoid concurrent use of live vaccines [see Warnings and Precautions (5.4)].

8. USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Risk Summary. Available data on TILA-278 use in pregnant women are insufficient to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. Human immunoglobulin G (IgG) antibodies are known to cross the placenta; therefore, TILA-278 may be transmitted from the mother to the developing fetus, with transfer increasing during the second and third trimesters. Consistent with ICH S6(R1), reproductive and developmental toxicity is characterized in the cynomolgus monkey, the pharmacologically relevant species; available findings were consistent with the pharmacologic activity of the antibody and did not identify a specific developmental hazard at clinically relevant exposures [see Nonclinical Toxicology (13.1)].

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defects, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2%–4% and 15%–20%, respectively.

8.2 Lactation

Risk Summary. There are no data on the presence of tilazumig in human milk, the effects on the breastfed infant, or the effects on milk production. Maternal IgG is present in human milk. The developmental and health benefits of breastfeeding should be considered along with the mother's clinical need for TILA-278 and any potential adverse effects on the breastfed infant from TILA-278 or from the underlying maternal condition.

8.3 Females and Males of Reproductive Potential

No human data are available on the effect of TILA-278 on fertility. Dedicated fertility studies were not conducted; repeat-dose toxicology in cynomolgus monkeys included assessment of reproductive organs and did not identify effects of concern, consistent with ICH S6(R1) for this class.

8.4 Pediatric Use

The safety and effectiveness of TILA-278 in pediatric patients have not been established.

8.5 Geriatric Use

Clinical studies of TILA-278 did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. In general, dose selection for an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal, or cardiac function and of concomitant disease.

8.6 Renal and Hepatic Impairment

No dedicated studies were conducted in patients with renal or hepatic impairment. As a monoclonal antibody eliminated principally by catabolism and target-mediated pathways rather than by renal or hepatic clearance, no dosage adjustment is anticipated on the basis of renal or hepatic impairment [see Clinical Pharmacology (12.3)].

10. OVERDOSAGE

There is no clinical experience with overdosage of TILA-278. In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment.

11. DESCRIPTION

Tilravimab-xxxx is a recombinant, humanized immunoglobulin G1 (IgG1) bispecific monoclonal antibody produced in a Chinese hamster ovary (CHO) cell line by recombinant DNA technology. One antigen-binding arm functions as an antagonist of TL1A (TNFSF15); the second arm functions as an agonist at the interleukin-22 receptor (IL-22R). The antibody has an approximate molecular weight of 150 kDa.

TILA-278 injection is a sterile, preservative-free, clear to slightly opalescent, colorless to pale yellow solution for subcutaneous administration. Each single-dose prefilled syringe/autoinjector delivers 450 mg of tilazumig in 3 mL (150 mg/mL). Each mL contains tilazumig (450 mg) and the following excipients: a buffering system, a stabilizer, and polysorbate, at pH . The finished drug product is manufactured to comply with compendial and product-specific specifications for identity, content, purity/impurities (including aggregates, charge variants, and glycosylation profile), and potency (dual bioassays confirming anti-TL1A neutralization and IL-22R agonist activity), as detailed in Module 3.2.P.5.

12. CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

TILA-278 is a bispecific antibody that simultaneously engages two complementary pathways relevant to UC. Antagonism of TL1A (TNFSF15) blocks TL1A–DR3 (death receptor 3) signaling, dampening TH1/TH17-driven mucosal inflammation and pro-fibrotic signaling in the intestine. Agonism at the IL-22 receptor on intestinal epithelial cells promotes epithelial regeneration, antimicrobial peptide production, and mucosal-barrier repair. The combined effect is anti-inflammatory activity coupled with promotion of mucosal healing. The precise contribution of each mechanism to clinical efficacy in UC has not been fully characterized.

12.2 Pharmacodynamics

Consistent with its mechanism, treatment with TILA-278 was associated with reductions in markers of intestinal inflammation (including fecal calprotectin and C-reactive protein) and with endoscopic and histologic improvement over the induction period. The exposure–response relationship for clinical remission was dose-ordered across the placebo, Low, and High groups [see Clinical Studies (14)].

Cardiac electrophysiology. A dedicated QT study was not conducted. Consistent with ICH E14/S7B and ICH S6(R1), thorough QT assessment is not warranted for a monoclonal antibody with no expected direct ion-channel activity; the waiver rationale is supported by the nonclinical safety pharmacology package.

12.3 Pharmacokinetics

The pharmacokinetics of TILA-278 are characterized by target-mediated drug disposition (TMDD), resulting in nonlinear (dose-dependent) clearance at lower concentrations and approximately linear disposition at concentrations that saturate target binding.

• Absorption: Following subcutaneous administration, the estimated absolute bioavailability is approximately 65%, with maximum serum concentrations reached at a median of ~6 days.
• Distribution: The estimated volume of distribution is consistent with distribution largely confined to the vascular and interstitial spaces (2000 L).
• Elimination: TILA-278 is eliminated by a combination of nonspecific proteolytic catabolism and saturable target-mediated clearance. The terminal half-life at steady state is approximately 19 days.
• Specific populations: Population pharmacokinetic analyses did not identify clinically meaningful effects of age, sex, or body weight requiring dosage adjustment. Renal and hepatic impairment are not expected to affect clearance [see Use in Specific Populations (8.6)].
• Immunogenicity: Anti-drug antibodies did not have a clinically meaningful effect on exposure over the induction period [see Adverse Reactions (6.2)].

13. NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Consistent with ICH S6(R1), no genotoxicity or carcinogenicity studies were conducted with TILA-278; such studies are generally not warranted for monoclonal antibodies. The general toxicology program comprised repeat-dose subcutaneous studies in the cynomolgus monkey (a pharmacologically relevant species), a tissue cross-reactivity assessment using human and cynomolgus tissues, and safety pharmacology endpoints incorporated into the repeat-dose studies. Because the human targets are not pharmacologically engaged in conventional rodents, pharmacology was characterized in disease models using a surrogate/knock-in approach. Findings in the cynomolgus monkey were limited to expected pharmacologic effects and injection-site changes, with no unexpected target-organ toxicity. Fertility was not evaluated in dedicated studies; reproductive organ histopathology in repeat-dose studies revealed no findings of concern.

14. CLINICAL STUDIES

The efficacy of TILA-278 for the induction of clinical remission in moderately to severely active UC was established in Study TILA278-201 (Protocol TILA278-201), a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, 12-week induction study.

Design and population. Of 1,700 patients screened, 900 adults with moderately to severely active UC were randomized 1:1:1 to TILA-278 High (450 mg; n=299), TILA-278 Low (150 mg; n=300), or placebo (n=301) administered subcutaneously. Randomization was stratified by baseline modified Mayo severity and by prior biologic exposure. Study visits occurred at Weeks 0, 2, 4, 8, and 12.

Primary endpoint. Clinical remission at Week 12, defined as a modified Mayo score ≤2 with no individual subscore >1.

Efficacy results (full analysis set). The primary endpoint was met, with a statistically significant and dose-ordered benefit for both TILA-278 doses over placebo.

Table 3. Clinical Remission at Week 12 (Full Analysis Set)

Endpoint	TILA-278 High	TILA-278 Low	Placebo
Clinical remission at Week 12, n/N (%)	106/284 (37.3%)	46/283 (16.2%)	2/273 (0.7%)

The difference in remission rates versus placebo was clinically meaningful for both doses, with the High dose achieving the greatest response.

Table 4. Change From Baseline in Modified Mayo Score at Week 12 (Full Analysis Set; ANCOVA)

Statistic	TILA-278 High	TILA-278 Low	Placebo
LS-mean change from baseline	−3.36	−2.76	−1.00
LS-mean difference vs placebo (95% CI)	−2.36 (−2.49, −2.23)	−1.77 (−1.90, −1.64)	—
p-value vs placebo	<0.0001	<0.0001	—

Both TILA-278 doses produced statistically significant reductions in the modified Mayo score compared with placebo (p<0.0001), with a dose-ordered effect supporting the recommended induction dosage [see Dosage and Administration (2.2)].

16. HOW SUPPLIED/STORAGE AND HANDLING

How Supplied. TILA-278 injection is a clear to slightly opalescent, colorless to pale yellow solution supplied as:

Presentation	Strength	NDC
Single-dose prefilled syringe (carton of 1)	450 mg/3 mL (150 mg/mL)	NDC
Single-dose prefilled autoinjector (carton of 1)	450 mg/3 mL (150 mg/mL)	NDC

Storage and Handling.

• Store refrigerated at 2°C to 8°C (36°F to 46°F) in the original carton to protect from light. Do not freeze. Do not shake.
• If needed, TILA-278 may be kept at room temperature up to 25°C (77°F) for a single period of up to days in the original carton; discard if not used within that period.
• Keep out of the reach of children.

17. PATIENT COUNSELING INFORMATION

Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and Instructions for Use).

• Infections. Advise patients that TILA-278 may lower the ability to fight infections. Instruct patients to contact their healthcare provider if they develop signs or symptoms of infection [see Warnings and Precautions (5.1)].
• Hypersensitivity. Advise patients to seek immediate medical attention if they experience any symptoms of a serious allergic reaction [see Warnings and Precautions (5.2)].
• Injection-site reactions. Inform patients that injection-site reactions may occur and are usually mild-to-moderate; advise rotation of injection sites [see Warnings and Precautions (5.3), Dosage and Administration (2.3)].
• Immunizations. Advise patients to complete age-appropriate immunizations before starting TILA-278 and to avoid live vaccines during treatment [see Warnings and Precautions (5.4)].
• Administration. Provide training on proper subcutaneous injection technique, preparation, and safe disposal of syringes/autoinjectors for patients who will self-administer or caregivers who will administer TILA-278 [see Dosage and Administration (2.3)].
• Pregnancy. Advise patients to inform their healthcare provider if they are pregnant, become pregnant, or intend to become pregnant [see Use in Specific Populations (8.1)].

Manufactured for and distributed by: Virtual Biopharma Inc. U.S. License No.

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End of draft Prescribing Information (eCTD 1.14.1.3). The annotated draft labeling at eCTD 1.14.1.2 cross-references each clinical statement in this document to its supporting data in Modules 2.5, 2.7, and 5, and each nonclinical and quality statement to Modules 2.4, 2.6, and 3.