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Periodic Benefit-Risk Evaluation Report (TILA-278)

Document ID: PSUR-001
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E2C(R2)

Periodic Benefit-Risk Evaluation Report (PBRER/PSUR) — TILA-278

Periodic benefit-risk evaluation for TILA-278: worldwide exposure, signal and risk evaluation, and an integrated benefit-risk conclusion for the reporting interval. ICH E2C(R2).

TILA-278 is a humanized, bispecific IgG1 monoclonal antibody that simultaneously antagonizes TNF-like ligand 1A (TL1A) and agonizes the interleukin-22 receptor (IL-22R), administered subcutaneously for the treatment of moderate-to-severe ulcerative colitis (UC). The product is being developed by Virtual Biopharma Inc. and remains investigational in all territories; a Biologics License Application under 21 CFR Part 601 is anticipated. Because the product holds no marketing authorization, post-authorization sections of the ICH E2C(R2) template are presented as "not applicable," and cumulative exposure is derived exclusively from the clinical development programme. This report consolidates cumulative and interval data with a data lock point (DLP) of 14 January 2026, covering the reporting interval 15 January 2025 through 14 January 2026; the Development International Birth Date (DIBD) is 15 January 2025.

1. Introduction

TILA-278 couples two complementary, tissue-restricted mechanisms relevant to UC pathophysiology. TL1A (the TNFSF15 gene product) drives mucosal inflammation and fibrosis through DR3 signaling on effector and regulatory lymphocytes; antagonism of TL1A is expected to be anti-inflammatory and anti-fibrotic. IL-22R agonism acts on the intestinal epithelial compartment to promote epithelial regeneration, mucus and antimicrobial peptide production, and barrier restitution, supporting mucosal healing. The bispecific design is intended to dampen the inflammatory drive while actively promoting epithelial repair within the same molecule.

This document is prepared in the PBRER format under ICH E2C(R2) to provide an integrated, periodic benefit-risk evaluation of the accumulated clinical, non-clinical, and literature data. The reporting interval encompasses the completion of the pivotal Phase 2b induction study, TILA278-201. No new safety concern arising in the interval altered the reference safety information.

2. Worldwide Marketing Approval Status

TILA-278 has not been granted marketing authorization in any country and is investigational worldwide. During the reporting interval the product was administered under clinical trial authorizations supporting the Phase 2b programme. No applications for marketing authorization were approved, refused, withdrawn, or suspended in the interval. A BLA under 21 CFR Part 601 is planned following confirmatory development.

3. Actions Taken in the Reporting Interval for Safety Reasons

No actions were taken for safety reasons during the reporting interval. There were no clinical hold, protocol amendment for safety, dosing restriction, formulation change, recruitment suspension, informed-consent revision, or health-authority-requested labeling change attributable to an emergent safety concern. No urgent safety measures were implemented.

4. Changes to Reference Safety Information

The reference safety information (RSI) for this evaluation is the currently effective Investigator's Brochure (IB) list of expected serious adverse reactions. No changes were made to the RSI during the reporting interval. No adverse reaction was reclassified between listed and unlisted, and no new important identified risk was added to the RSI in the interval.

5. Estimated Exposure and Use Patterns

Because TILA-278 is investigational, there is no marketing exposure. Cumulative clinical-trial exposure derives from the single completed study, TILA278-201, and equals the interval exposure.

• Screened: 1700 subjects.
• Randomized: 900 subjects, 1:1:1 to the High-dose, Low-dose, and Placebo arms (299 High / 300 Low / 301 Placebo).
• Full Analysis Set (FAS): 840 subjects (284 High / 283 Low / 273 Placebo).
• Subjects randomized to active TILA-278 totaled 599 (299 High + 300 Low); 301 were randomized to placebo.

Exposure was subcutaneous over a 12-week induction period under double-blind conditions. No off-label, pediatric, or special-population marketing use exists. Dose selection in the programme spans the High and Low regimens evaluated in TILA278-201.

6. Data in Summary Tabulations

Serious adverse events (SAEs) from the clinical development programme are compiled cumulatively by System Organ Class and preferred term in the appended summary tabulations. Consistent with the mechanism and the subcutaneous route, the most frequently reported treatment-emergent events were injection-site reactions and events consistent with the underlying UC (e.g., disease flare). There were no fatal outcomes attributable to study drug in the reporting interval. Because the product is not marketed, there are no spontaneous post-marketing case reports, and no interval or cumulative post-marketing summary tabulations are applicable. Blinded aggregate review during conduct identified no imbalance meeting a predefined signaling threshold.

7. Summaries of Significant Safety Findings from Clinical Trials during the Reporting Interval

TILA278-201 — a Phase 2b, randomized, double-blind, placebo-controlled, 1:1:1, 12-week induction study — completed during the interval and is the principal source of new information. The overall safety profile was consistent with a subcutaneously administered immunomodulatory monoclonal antibody. Injection-site reactions were the most common product-related events and were predominantly mild to moderate and self-limited. No dose-limiting toxicity, no clustering of serious infections, and no signal of hepatic, pancreatic, or dermatologic epithelial toxicity attributable to IL-22R agonism were identified over the induction period. Anti-drug antibody (ADA) formation was monitored throughout; observed immunogenicity did not translate into a discernible impact on the benefit-risk balance over 12 weeks. No new important identified risk emerged.

8. Findings from Non-interventional Studies

No non-interventional (observational) studies were ongoing or completed during the reporting interval. This section is not applicable.

9. Information from Other Clinical Trials and Sources

No other sponsor-conducted interventional trials contributed data during the interval beyond TILA278-201. No information was received from other manufacturers, from clinical trial partners, or from investigator-initiated research that would alter the safety characterization of TILA-278.

10. Non-clinical Data

The non-clinical package was conducted in accordance with ICH S6(R1) for biotechnology-derived pharmaceuticals. The cynomolgus monkey is the sole pharmacologically relevant toxicology species, based on demonstrated cross-reactivity and comparable pharmacology at both the TL1A and IL-22R binding arms; rodents are not pharmacologically relevant and were not used for pivotal toxicology. Repeat-dose toxicology, safety pharmacology endpoints integrated into the general toxicology design, tissue cross-reactivity, and toxicokinetics support the clinical programme. Pharmacokinetics are governed by target-mediated drug disposition (TMDD), yielding non-linear disposition at lower concentrations consistent with target engagement at both arms; immunogenicity (ADA, including neutralizing antibody assessment) is monitored as a relevant covariate of exposure.

Consistent with ICH S6(R1), standalone genotoxicity and carcinogenicity studies were not conducted and are not warranted for a monoclonal antibody of this class; likewise, dedicated hERG assays and a thorough QT study were not performed, as direct ion-channel or cardiac repolarization liability is not expected for a large, target-specific protein therapeutic. The absence of these studies is scientifically justified and does not represent a data gap.

Quality and CMC attributes support the non-clinical and clinical interpretation: the molecule is produced by CHO cell culture with a downstream process anchored by Protein A capture followed by polishing chromatography. Viral safety, cell-substrate characterization, stability, and specification-setting follow ICH Q5A(R2) (viral safety and adventitious agents), ICH Q5C (stability of biotechnological products), and ICH Q6B (specifications and test procedures for biotechnological/biological products). No non-clinical finding in the interval changed the risk characterization.

11. Literature

The published literature on TL1A/DR3 and IL-22/IL-22R biology in inflammatory bowel disease was reviewed for the interval. Literature continues to support TL1A antagonism as an anti-inflammatory and anti-fibrotic strategy and IL-22R agonism as an epithelial-restitution and mucosal-healing strategy, and to flag the theoretical, on-target considerations of sustained epithelial IL-22R signaling (e.g., in hepatic, pancreatic, and dermatologic epithelia where IL-22R is expressed). No individual case report or literature safety finding in the interval met criteria for a new signal or required RSI revision.

12. Other Periodic Reports

The corresponding Development Safety Update Report (DSUR) for the programme covers the same development activities; this PBRER-format evaluation is consistent with, and cross-references, that periodic safety reporting. No discrepancy exists between the periodic reports.

13. Lack of Efficacy in Controlled Clinical Trials

Lack of efficacy is not a safety concern for this product in the interval. In the controlled Phase 2b study the primary endpoint was met with a clear dose-ordered separation from placebo (see Section 17). No finding of lack of efficacy adversely affected the benefit-risk balance.

14. Late-Breaking Information

No late-breaking information with a potential impact on the benefit-risk assessment was received between the data lock point and finalization of this report.

15. Overview of Signals: New, Ongoing, or Closed

No new signals were identified, evaluated, or closed during the reporting interval. There are no ongoing signals under evaluation at the data lock point. Blinded and aggregate safety review across the programme did not surface a validated signal.

16. Signal and Risk Evaluation

16.1 Summary of Safety Concerns. The safety specification, informed by mechanism, class knowledge, and observed data, is summarized below.

Category	Concern
Important identified risks	Injection-site reactions (subcutaneous administration).
Important potential risks	Serious and opportunistic infections (immunomodulation via TL1A antagonism); immunogenicity leading to hypersensitivity or attenuated exposure/efficacy; on-target IL-22R–mediated epithelial proliferative effects (hepatic, pancreatic, dermatologic); malignancy with long-term immunomodulation.
Missing information	Long-term safety beyond the 12-week induction period; use in pregnancy and lactation; pediatric and elderly use; use in hepatic or renal impairment; concomitant use with other immunosuppressants; response to vaccination.

16.2 Signal Evaluation. No signal required formal evaluation in the interval; the events observed were anticipated for the route and class and did not exceed expected frequency or severity.

16.3 Evaluation of Risks and New Information. The 12-week controlled data did not upgrade any potential risk to an identified risk. Immunogenicity was detectable but without demonstrable impact on the benefit-risk balance over the induction period. TMDD-driven non-linear PK remains adequately characterized for the doses studied.

16.4 Characterisation of Risks. Injection-site reactions were generally mild to moderate, self-limited, and manageable. The potential risks remain theoretical or mechanism-based over the interval studied; their long-term characterization requires the planned confirmatory and maintenance data (missing information).

16.5 Effectiveness of Risk Minimisation. Only routine risk minimization (protocol-defined monitoring, IB, and informed consent) applies at this investigational stage; no additional risk minimization measures were required in the interval.

17. Benefit Evaluation

17.1 Important Baseline Efficacy/Effectiveness Information. The therapeutic rationale is dual-mechanism control of UC: TL1A antagonism to reduce inflammation and fibrosis, and IL-22R agonism to drive epithelial and mucosal healing.

17.2 Newly Identified Information on Efficacy/Effectiveness. In TILA278-201, the primary endpoint of clinical remission (modified Mayo score ≤ 2 with no individual subscore > 1) at Week 12 was achieved in 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, demonstrating a clear dose-ordered, clinically meaningful separation from placebo. Key secondary endpoints were concordant: the LS-mean change from baseline in modified Mayo score was −3.36 (High), −2.76 (Low), and −1.00 (Placebo), corresponding to placebo-adjusted differences of −2.36 (High) and −1.77 (Low). Endoscopic improvement was observed in 48.9%, 27.9%, and 6.2% of the High-dose, Low-dose, and Placebo groups, respectively.

17.3 Characterisation of Benefits. The benefit is a robust, dose-dependent induction of clinical remission accompanied by symptomatic (modified Mayo) and objective endoscopic improvement, consistent with the intended dual mechanism, in a moderate-to-severe UC population with high unmet need.

18. Integrated Benefit-Risk Analysis for Approved Indications

18.1 Benefit-Risk Context. No approved indication exists; the integrated analysis is presented for the investigational induction indication in moderate-to-severe UC. Moderate-to-severe UC carries substantial morbidity, and a mechanism that combines anti-inflammatory/anti-fibrotic TL1A antagonism with epithelium-restoring IL-22R agonism addresses complementary disease drivers.

18.2 Benefit-Risk Analysis Evaluation. Over the 12-week induction interval, the benefit is substantial and objectively supported (primary remission 37.3% High vs 0.7% Placebo, with concordant modified Mayo LS-mean and endoscopic-improvement results), while the identified risk profile is limited principally to manageable injection-site reactions. The remaining concerns are potential or reflect missing long-term information rather than emergent harms. On the accumulated data at this data lock point, the benefit-risk balance for the investigational induction use is favorable.

19. Conclusions and Actions

The accumulated evidence at the data lock point supports a favorable benefit-risk balance for TILA-278 in the investigational induction treatment of moderate-to-severe UC. No new safety concern emerged, no change to the reference safety information was warranted, and no safety-related action was taken in the interval. No modification to the ongoing development plan, monitoring, or risk-management approach is required. Characterization of long-term safety and the potential risks identified in the safety specification will continue through planned confirmatory and maintenance studies.

20. Appendices

• Cumulative and interval summary tabulations of serious adverse events by System Organ Class and preferred term.
• Reference safety information (effective Investigator's Brochure) and RSI change log.
• Cumulative clinical-trial exposure listing (screened 1700; randomized 900; FAS 840).
• Cross-reference to the programme DSUR and to the non-clinical (ICH S6(R1)) and quality (ICH Q5A(R2), Q5C, Q6B) documentation.