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Development Safety Update Report (TILA-278)

Document ID: DSUR-001
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E2F

Development Safety Update Report (DSUR) — TILA-278

This Development Safety Update Report (DSUR) presents a comprehensive, cumulative and interval annual review of the safety of TILA-278 (INN: tilarudimab), a recombinant humanised IgG1 bispecific monoclonal antibody combining anti-TL1A (TNFSF15) antagonism with IL-22 receptor agonism, in development by Virtual Biopharma Inc. for the treatment of adults with moderately-to-severely active ulcerative colitis (UC). It has been prepared in accordance with ICH E2F and describes the worldwide development programme, the cumulative and interval subject exposure, the actions taken during the reporting period for safety reasons, line listings and summary tabulations of serious adverse events, significant clinical and non-clinical findings, and an integrated overall safety assessment for the reporting interval. The molecule is produced by fed-batch culture of a stably transfected Chinese hamster ovary (CHO) cell line with Protein-A affinity capture and orthogonal polishing chromatography, and is administered by subcutaneous (SC) injection; its viral safety, stability and specifications are governed by ICH Q5A(R2), Q5C and Q6B, and its non-clinical evaluation by ICH S6(R1). The primary source of clinical safety and efficacy data in this interval is the completed pivotal Phase 2b induction study TILA278-201.

Report Identification

Item	Detail
Sponsor	Virtual Biopharma Inc.
Investigational medicinal product	TILA-278 (INN: tilarudimab)
Product class / modality	Recombinant humanised IgG1 bispecific monoclonal antibody (CHO cell culture; SC administration)
Mechanism of action	Dual mechanism from a single bispecific molecule: TL1A (TNFSF15) antagonism (anti-inflammatory, anti-fibrotic) and IL-22 receptor agonism (epithelial regeneration and mucosal-barrier repair)
Development indication	Moderately-to-severely active ulcerative colitis in adults
Development International Birth Date (DIBD)	01 July 2025 (date of first clinical-trial authorisation)
Reporting interval	01 July 2025 to 30 June 2026
Data lock point (DLP)	30 June 2026
Sequence	This is the first DSUR for TILA-278; interval and cumulative data are therefore coextensive
Reference Safety Information (RSI)	Investigator's Brochure for TILA-278 (current Edition 3.0), section on expected serious adverse reactions
Applicable standard	ICH E2F

Executive Summary

During the reporting interval, the TILA-278 development programme progressed from Phase 1 to the completion of the pivotal Phase 2b induction study TILA278-201. Cumulatively, 671 subjects have received at least one dose of TILA-278 and 325 have received placebo across the programme, corresponding to approximately 140 patient-years of active exposure. In TILA278-201, 900 adults with moderate-to-severe UC were randomised 1:1:1 to TILA-278 High (299), TILA-278 Low (300), or placebo (301); the study met its primary endpoint with a large, statistically significant, dose-ordered effect on Week 12 clinical remission (37.3% [106/284] High and 16.2% [46/283] Low versus 0.7% [2/273] placebo).

No action was taken during the reporting interval for safety reasons: no study was suspended or terminated for safety, no dose or protocol modification was made for safety reasons, and no regulatory authority imposed a restriction. TILA-278 was generally well tolerated, with no dose-dependent safety signal. Serious adverse events were infrequent and were numerically fewer in the combined active arms than on placebo (3 High, 0 Low, 4 placebo); all three deaths in the programme (2 High, 0 Low, 1 placebo) were assessed by the investigator as unrelated to study treatment. No serious adverse event in the TILA-278 arms was assessed as related to study treatment, so no serious adverse reactions and no suspected unexpected serious adverse reactions (SUSARs) were reported for TILA-278 during the interval. The principal drug-attributable finding was mild-to-moderate, self-limited injection-site reactions, an expected observation for a subcutaneous biologic. No new safety signal emerged from the clinical, non-clinical, or literature review. The benefit-risk balance of TILA-278 in moderate-to-severe UC remains positive, and continued development — including the planned long-term maintenance and open-label extension study TILA278-301 — is supported.

1. Introduction

TILA-278 is a first-in-class, recombinant, humanised IgG1 bispecific monoclonal antibody engineered to engage two complementary pathways of intestinal immunopathology through independent antigen-binding arms. One arm is an antagonist of TL1A (TNFSF15), which signals through death receptor 3 (DR3) to amplify TH1/TH17-driven mucosal inflammation and to promote intestinal fibrosis; antagonism is intended to reduce inflammatory cytokine output and pro-fibrotic remodelling. The second arm is an agonist of the IL-22 receptor (IL-22RA1/IL-10RB) on intestinal epithelium, signalling via STAT3 to drive epithelial regeneration, antimicrobial-peptide and mucin production, and mucosal-barrier repair. The design intent is a single agent that couples anti-inflammatory activity with active mucosal healing, addressing both the inflammatory drive and the epithelial-repair deficit that characterise UC.

The drug substance is expressed in a CHO cell line and purified by Protein-A affinity capture followed by orthogonal polishing chromatography and a dedicated viral-clearance train; the drug product is a sterile, preservative-free solution for SC injection presented in single-use prefilled-syringe and prefilled-pen (autoinjector) configurations. Because both target epitopes are human-specific, conventional rodents are not pharmacologically relevant, and the cynomolgus monkey is the sole relevant species for repeat-dose toxicology, consistent with ICH S6(R1). Pharmacokinetics reflect a component of target-mediated drug disposition (TMDD) at lower, sub-saturating concentrations, transitioning toward linearity as target is saturated; as a monoclonal antibody, TILA-278 is catabolised to peptides and amino acids and is not a substrate for cytochrome-P450 metabolism or renal elimination. Anti-drug antibody (ADA) formation is a relevant consideration and is characterised with a validated tiered assay strategy (screening, confirmatory, titre, and neutralising-antibody tiers).

This DSUR is the first for TILA-278. Its purpose is to present a comprehensive annual review of the worldwide safety information accrued during the reporting interval, to examine whether that information is consistent with the current knowledge of the product's safety, and to describe actions proposed or taken to address safety concerns. Being the inaugural DSUR, the interval covered (01 July 2025 to 30 June 2026) and the cumulative development experience to the DLP (30 June 2026) coincide. The report is intended to support continued clinical development and the planned marketing application (a Biologics License Application under 21 CFR 601 in the United States, with corresponding applications in other regions).

2. Worldwide Marketing Approval Status

TILA-278 is an investigational product and has not been granted marketing authorisation in any country or region. It is not approved, marketed, or otherwise commercially available anywhere in the world, and there is therefore no cumulative post-marketing exposure at the DLP of this report. Clinical development is being conducted under the applicable clinical-trial authorisations, including an Investigational New Drug (IND) application in the United States (21 CFR 312) and equivalent clinical-trial authorisations in other regions.

3. Actions Taken in the Reporting Period for Safety Reasons

No action was taken during the reporting interval for safety reasons in relation to any clinical trial or to the investigational product as a whole. Specifically, during the interval:

• no clinical trial was suspended, terminated early, or placed on clinical hold for safety reasons;
• no dose, dosing regimen, or route of administration was modified for safety reasons;
• no protocol amendment was implemented to manage a safety concern, and no change was made to study-population eligibility, monitoring, or informed consent for safety reasons;
• no restriction was imposed on distribution, and no failure to obtain or renewal refusal of a clinical-trial authorisation occurred on safety grounds;
• no formal safety-driven change was made to the manufacturing process; the CHO-based process, Protein-A capture and polishing chromatography, and the associated viral-safety, stability and specification controls (ICH Q5A(R2), Q5C, Q6B) remained as characterised, and no quality or manufacturing issue with safety implications arose; and
• the independent Data Safety Monitoring Board (DSMB) that reviewed accumulating unblinded safety data from TILA278-201 recommended continuation without modification at each scheduled review.

No urgent safety measure, Dear Investigator/Health-Care-Professional communication, or safety-related labelling restriction was required during the interval.

4. Changes to Reference Safety Information

The Reference Safety Information (RSI) used for the assessment of expectedness of serious adverse reactions is the "expected serious adverse reactions" listing within the current Investigator's Brochure (IB) for TILA-278. During the reporting interval the IB was revised (to Edition 3.0) to incorporate the completed non-clinical package and the efficacy and safety results of the pivotal induction study TILA278-201.

No new expected serious adverse reaction was added to the RSI list during the interval. This reflects the clinical experience accrued: no serious adverse event observed in the TILA-278 arms was assessed by the investigator as related to study treatment, and the principal identified adverse drug reaction — injection-site reactions — is non-serious. The list of expected serious adverse reactions in the RSI therefore continues to be informed principally by the mechanism of action and the recognised class effects of immunomodulatory biologics (serious and opportunistic infection; hypersensitivity), which are carried as anticipated risks rather than as observed serious reactions. No change to the RSI during the interval altered the expectedness determination for any reported event.

5. Inventory of Clinical Trials Ongoing and Completed During the Reporting Period

The clinical development programme comprises the studies summarised below. During the reporting interval the Phase 1 first-in-human studies and the pivotal Phase 2b induction study were completed; the long-term maintenance and open-label extension study is in start-up.

Table 5-1. Inventory of interventional clinical trials (cumulative to DLP)

Study	Phase / design	Population	Randomisation / dosing	Enrolment (dosed)	Status at DLP
TILA278-101	Phase 1, single-ascending-dose, randomised, double-blind, placebo-controlled	Healthy adults	Ascending SC single doses vs placebo	56 (42 TILA-278 / 14 placebo)	Completed
TILA278-102	Phase 1, multiple-ascending-dose, randomised, double-blind, placebo-controlled	Healthy adults	Repeat SC doses vs placebo	40 (30 TILA-278 / 10 placebo)	Completed
TILA278-201	Phase 2b, randomised, double-blind, placebo-controlled, parallel-group, 12-week induction	Moderate-to-severe UC (baseline modified Mayo 4–9; ages 18–75)	1:1:1 to TILA-278 High / TILA-278 Low / placebo; stratified by baseline modified Mayo severity and prior biologic exposure; assessments at Weeks 0, 2, 4, 8, 12	900 (299 High / 300 Low / 301 placebo)	Completed during interval
TILA278-301	Long-term maintenance and open-label extension (controlled maintenance followed by OLE)	Moderate-to-severe UC responders/remitters from induction	Maintenance dosing over ≥ 52 weeks	Not yet dosed	In start-up

TILA278-201 was conducted at multiple investigational sites across several regions under the applicable clinical-trial authorisations. A tabular listing of all studies is maintained in Module 5.2.

6. Estimated Cumulative Exposure

6.1 Cumulative Subject Exposure in the Development Programme

Because this is the first DSUR, cumulative exposure since the DIBD is coextensive with interval exposure. Across the development programme, 671 subjects have received at least one dose of TILA-278 and 325 subjects have received placebo (996 subjects dosed in total). The great majority of active exposure, and essentially all repeat-dose exposure of clinical duration, derives from the pivotal Phase 2b induction study; the Phase 1 single- and multiple-ascending-dose studies contributed short-duration exposure in a limited number of healthy adults.

Table 6.1-1. Cumulative subject exposure by study (subjects dosed)

Study	Population	TILA-278 (active), n	Placebo, n	Total dosed, n
TILA278-101 (SAD)	Healthy adults	42	14	56
TILA278-102 (MAD)	Healthy adults	30	10	40
TILA278-201 (Phase 2b)	Moderate-to-severe UC	599	301	900
Cumulative	—	671	325	996

In TILA278-201, all randomised subjects who received at least one dose constituted the safety population (299 High, 300 Low, 301 placebo). Study treatment was administered subcutaneously over the 12-week induction period using identical injection schedules and volumes across arms to preserve the double blind, with a High dose of 300 mg and a Low dose of 150 mg per administration. Exposure in this study corresponds to approximately 68.7 patient-years (High), 68.9 patient-years (Low), and 69.1 patient-years (placebo) — approximately 137.6 patient-years of active TILA-278 exposure. Including the short-duration Phase 1 exposure, cumulative active exposure across the programme is approximately 140 patient-years.

Table 6.1-2. Extent of exposure in the pivotal study TILA278-201 (safety population)

Exposure category	TILA-278 High (N=299)	TILA-278 Low (N=300)	Placebo (N=301)	Total active
Subjects dosed (≥ 1 dose)	299	300	301	599
Route of administration	Subcutaneous	Subcutaneous	Subcutaneous	—
Planned treatment duration	12 weeks (induction)	12 weeks (induction)	12 weeks (induction)	—
Approximate person-time	~68.7 patient-years	~68.9 patient-years	~69.1 patient-years	~137.6 patient-years

Table 6.1-3. Demographic distribution of active exposure (TILA278-201, active arms combined)

Category	Proportion of exposed subjects
Age < 65 years	~92%
Age ≥ 65 years	~8%
Female / Male	~44% / ~56%
Prior biologic exposure (stratification factor)	~50%

Cumulative exposure is limited to a 12-week induction period in an adult population (18–75 years), predominantly younger than 65 years. This directly informs the long-term-safety and special-population items carried as missing information in the risk documentation and addressed by the planned pharmacovigilance activities.

6.2 Patient Exposure from Marketing Experience

Not applicable. TILA-278 is not authorised or marketed in any region; there is no post-marketing exposure to report.

7. Data in Line Listings and Summary Tabulations

7.1 Reference Information

Adverse events were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 28.1. Serious adverse events (SAEs) and serious adverse reactions are presented by MedDRA System Organ Class (SOC) and Preferred Term. Because the pivotal study TILA278-201 is completed and its treatment allocation has been unblinded, cumulative summary tabulations are presented by treatment arm. Detailed subject-level line listings and the full summary tabulations are provided in the appendices to this report; the tabulations below summarise the serious-event experience.

7.2 Line Listings of Serious Adverse Reactions During the Reporting Period

A line listing in this section is restricted to serious adverse reactions (SAEs assessed as at least possibly related to TILA-278) reported during the reporting interval. No serious adverse event in the TILA-278 arms of any study was assessed by the investigator as related to study treatment; on independent medical review by the sponsor's safety physician, and by the DSMB for the pivotal study, these assessments were confirmed. Accordingly, there are no serious adverse reactions to list for TILA-278 for the reporting interval, and no suspected unexpected serious adverse reaction (SUSAR) was identified or reported in any region. The serious adverse events that did occur (all assessed as unrelated) are captured in the cumulative summary tabulation in Section 7.3.

7.3 Cumulative Summary Tabulations of Serious Adverse Events

Serious adverse events across the programme were infrequent and were numerically fewer in the combined active arms than on placebo. No SAE was reported in the Phase 1 single- and multiple-ascending-dose studies. In the pivotal induction study TILA278-201, SAEs were reported in 3 subjects (1.0%) in the High-dose arm, no subjects (0%) in the Low-dose arm, and 4 subjects (1.3%) in the placebo arm. The serious events did not cluster within any single MedDRA System Organ Class in the active arms, and none in the active arms was assessed as related to study treatment.

Table 7.3-1. Cumulative summary of serious adverse events and deaths (subjects, by treatment)

Category, n (%)	TILA-278 High (N=299)	TILA-278 Low (N=300)	Placebo (N=301)
Subjects with ≥ 1 serious adverse event	3 (1.0)	0 (0.0)	4 (1.3)
Subjects with ≥ 1 serious adverse reaction (related SAE)	0 (0.0)	0 (0.0)	0 (0.0)
Deaths	2 (0.7)	0 (0.0)	1 (0.3)

Three deaths occurred during the programme, all in the pivotal study: two subjects in the TILA-278 High-dose arm (0.7%), none in the Low-dose arm, and one subject in the placebo arm (0.3%). Each fatal event was reported as an SAE and was assessed by the investigator as unrelated to study treatment; the causality determinations were confirmed on independent sponsor review and by the DSMB. The determinations were based on the temporal relationship to dosing, the presence of contributory intercurrent and comorbid conditions in a moderate-to-severe chronic inflammatory disease population, and the absence of any mechanistic or pharmacological link to TL1A antagonism or IL-22 receptor agonism. No fatal event involved a serious opportunistic infection, a malignancy, or any other outcome that would suggest a class- or mechanism-related effect of TILA-278, and the deaths were not temporally clustered and shared no common aetiology or SOC pattern. The distribution of serious events and deaths is consistent with the background morbidity and mortality of a moderate-to-severe UC population rather than with a treatment-attributable signal.

8. Significant Findings from Clinical Trials During the Reporting Period

8.1 Completed Clinical Trials

Phase 1 (TILA278-101, TILA278-102). The first-in-human single- and multiple-ascending-dose studies characterised the safety, tolerability, and pharmacokinetics of TILA-278 in healthy adults and supported dose selection for Phase 2b. Pharmacokinetics were consistent with a subcutaneously administered IgG1 antibody exhibiting a component of TMDD at lower doses with a transition toward linearity at higher, target-saturating doses; SC bioavailability was of the order of 60% with a terminal half-life of approximately 2–3 weeks, supporting the induction dosing interval. No SAE, no death, and no dose-limiting safety finding were observed; local injection-site tolerability was the principal observation. These studies did not identify any safety concern that would preclude continued development.

Pivotal Phase 2b induction study (TILA278-201). This study was completed during the reporting interval and is the most significant clinical finding of the period. Of 1700 adults screened, 900 with moderate-to-severe UC (baseline modified Mayo 4–9) were randomised 1:1:1 to TILA-278 High, TILA-278 Low, or placebo over a 12-week induction period, with efficacy analysed on the Full Analysis Set (FAS; 284 High / 283 Low / 273 placebo).

The study met its primary endpoint with a large, statistically significant, and clearly dose-ordered effect. Clinical remission (modified Mayo score ≤ 2, with no individual subscore > 1) at Week 12 was achieved by 37.3% (106/284) of High-dose and 16.2% (46/283) of Low-dose subjects versus 0.7% (2/273) of placebo subjects. The LS-mean change from baseline in modified Mayo score at Week 12 was −3.36 (High), −2.76 (Low), and −1.00 (placebo), corresponding to differences versus placebo of −2.36 (95% CI −2.49, −2.23) for High and −1.77 (95% CI −1.90, −1.64) for Low, both p < 0.0001. Endoscopic improvement was observed in 48.9% (High), 27.9% (Low), and 6.2% (placebo) of subjects. These outcomes are consistent with the dual mechanism of TL1A antagonism (anti-inflammatory/anti-fibrotic) and IL-22 receptor agonism (epithelial and mucosal healing).

From a safety perspective, TILA-278 was generally well tolerated with no dose-dependent safety signal. The proportion of subjects with treatment-emergent adverse events (TEAEs) was not higher on active treatment than on placebo: 109 subjects (36.5%) High, 131 subjects (43.7%) Low, and 130 subjects (43.2%) placebo. Most events were mild or moderate. The higher background event rate on placebo was largely accounted for by events reflecting inadequately controlled disease (worsening UC and disease-associated anaemia), consistent with the efficacy findings. The principal drug-attributable finding was injection-site reactions, reported more frequently on active SC treatment than on placebo, predominantly mild-to-moderate, transient, and local, without a meaningful excess of treatment discontinuation. Consistent with the immunomodulatory component of the mechanism, infection-related events (nasopharyngitis, upper respiratory tract infection) were monitored closely; no increase in serious or opportunistic infection was observed with active treatment, and there were no reports of active tuberculosis, hepatitis reactivation, or serious opportunistic infection over the induction period. SAEs, deaths, and discontinuations are summarised in Section 7.3 and Table 8.1-1.

Table 8.1-1. Overall safety summary, pivotal study TILA278-201 (safety population)

Category, n (%)	TILA-278 High (N=299)	TILA-278 Low (N=300)	Placebo (N=301)
Subjects with ≥ 1 TEAE	109 (36.5)	131 (43.7)	130 (43.2)
Subjects with ≥ 1 serious adverse event	3 (1.0)	0 (0.0)	4 (1.3)
Deaths (all assessed as unrelated)	2 (0.7)	0 (0.0)	1 (0.3)
Discontinued study treatment (any cause)	17 (5.7)	17 (5.7)	29 (9.6)

Study discontinuations were balanced between the active arms (5.7% each) and lower than on placebo (9.6%); the placebo excess was driven predominantly by lack of efficacy (worsening UC) rather than by adverse events. Injection-site reactions, the principal drug-attributable finding, did not commonly lead to discontinuation, and there was no pattern of AE-related withdrawal indicating a tolerability limitation for either dose over the 12-week induction period. Clinical-laboratory monitoring (haematology, serum chemistry including hepatic and renal parameters, and the inflammatory biomarkers C-reactive protein and faecal calprotectin) revealed no hepatic, renal, or haematological toxicity signal; there were no cases meeting Hy's Law criteria, and inflammatory biomarkers declined in the active arms in proportion to the improvement in modified Mayo score, corroborating mucosal healing.

8.2 Ongoing Clinical Trials

No interventional clinical trial was actively dosing subjects at the DLP. The long-term maintenance and open-label extension study TILA278-301 is in start-up and had not yet enrolled or dosed subjects at the DLP; no safety findings are therefore available from ongoing trials for this interval.

8.3 Long-term Follow-up

No long-term follow-up data beyond the 12-week induction period are yet available. Long-term safety — including serious and opportunistic infection, malignancy (with a pre-specified focus on epithelial/colorectal neoplasia given the IL-22 receptor agonist mechanism), and ADA incidence, persistence, and neutralising potential — will be characterised prospectively in the maintenance and open-label extension study TILA278-301.

8.4 Other Therapeutic Use of Investigational Drug

There was no other therapeutic use of TILA-278 during the reporting interval. No named-patient, compassionate-use, expanded-access, or emergency-use programme was in place, and no exposure occurred outside the clinical-trial protocols described above.

8.5 New Safety Data Related to Combination Therapies

TILA-278 is being developed as monotherapy delivering a dual mechanism from a single bispecific molecule; it is not co-formulated or co-developed with another investigational agent. No new safety data related to fixed combinations or investigational co-administration were generated during the interval. In TILA278-201, concomitant background UC medications permitted by protocol (for example, stable-dose aminosalicylates and, where applicable, corticosteroids being tapered) were consistent with the treatment of the underlying disease and did not reveal any interaction-related safety concern.

9. Safety Findings from Marketing Experience

Not applicable. TILA-278 is not authorised or marketed in any region, and there is no post-marketing safety experience to report at the DLP.

10. Non-clinical Data

No new non-clinical safety study was completed during the reporting interval, and no previously reported non-clinical finding was reinterpreted in a way that alters the clinical safety assessment. The non-clinical package supporting the programme was designed in accordance with ICH S6(R1) for biotechnology-derived pharmaceuticals. Because both target epitopes are human-specific, conventional rodents are not pharmacologically relevant; primary pharmacology was characterised in disease models using a species-appropriate surrogate/knock-in system, and pivotal repeat-dose toxicology was conducted by the intended SC route in the cynomolgus monkey — the sole relevant species — for up to 26 weeks.

The no-observed-adverse-effect level (NOAEL) was the highest dose tested, providing an exposure margin of approximately 10-fold over the anticipated clinical exposure; findings were limited to reversible injection-site observations and exaggerated pharmacology, with no target-organ toxicity of concern. Safety-pharmacology endpoints (cardiovascular, respiratory, and central nervous system), integrated into the repeat-dose programme, revealed no adverse effects. A tissue cross-reactivity study on human and cynomolgus tissue panels showed binding consistent with the known distribution of the targets and no unexpected off-tissue binding. Consistent with ICH S6(R1), standard genotoxicity and rodent carcinogenicity studies were not conducted, as they are not scientifically warranted for a monoclonal antibody; likewise, dedicated in vitro ion-channel (for example hERG) studies and a thorough-QT evaluation were not warranted for this modality, which is a large, target-specific antibody with no expectation of direct ion-channel interaction (ICH E14/S7B waiver rationale). The theoretical proliferative concern arising from sustained IL-22 receptor agonism on epithelial tissue was evaluated histopathologically in the chronic study, with no proliferative or neoplastic findings; it is carried forward as a monitored clinical potential risk rather than resolved by rodent bioassay. No new non-clinical signal emerged during the interval, and the manufacturing-quality controls governing viral safety, stability, and specifications (ICH Q5A(R2), Q5C, Q6B) remained as characterised without any quality finding of safety relevance.

11. Literature

A review of the scientific literature relevant to TILA-278, its molecular targets, and its therapeutic class was conducted for the reporting interval. Published literature on TL1A/DR3 biology continues to support the anti-inflammatory and anti-fibrotic rationale for TL1A antagonism in inflammatory bowel disease, and literature on IL-22 receptor signalling continues to support its role in epithelial regeneration and mucosal-barrier repair. Class-level pharmacovigilance considerations for immunomodulatory biologics used in immune-mediated inflammatory disease — principally serious and opportunistic infection and, over long latency, malignancy — remain consistent with the important potential risks already carried for TILA-278. No published report during the interval identified a new safety concern for TILA-278 or for its mechanism that would alter the current benefit-risk assessment or require a change to the reference safety information.

12. Other Development Safety Update Reports

TILA-278 contains a single active substance and is not co-developed under a shared development programme with another sponsor. No separate DSUR is prepared for any other indication, formulation, or combination of TILA-278; this report covers the entire development programme for the single investigational product. There are therefore no other contemporaneous DSURs whose findings need to be reconciled with this report.

13. Lack of Efficacy

The pivotal induction study TILA278-201 met its primary endpoint with a large, dose-ordered treatment effect (clinical remission 37.3% High and 16.2% Low versus 0.7% placebo), and there is no indication of lack of efficacy for TILA-278 that carries a safety implication for study participants. Lack of efficacy was observed, as expected, in the placebo arm, where the low remission rate and the higher frequency of worsening UC drove the excess of discontinuations; this reflects untreated disease activity rather than a safety concern attributable to TILA-278. No situation arose in which lack of efficacy of TILA-278 in a serious or life-threatening condition posed a safety risk to subjects during the interval.

14. Region-Specific Information

Clinical development is being conducted under region-specific clinical-trial authorisations, including an IND in the United States (21 CFR 312) and equivalent authorisations in other regions; the planned United States marketing application is a Biologics License Application under 21 CFR 601, with corresponding applications in other regions. Expedited safety reporting obligations were met in each region. Because no serious adverse event in the TILA-278 arms was assessed as related to study treatment, and none was both serious, unexpected, and suspected to be related, no suspected unexpected serious adverse reaction (SUSAR) was reported in any region during the interval; the cumulative SUSAR count for TILA-278 is zero. No region-specific safety issue, regulatory query, or authority-requested action arose during the interval that is not otherwise addressed in this report. Cumulative and interval subject exposure is presented in Section 6; region-specific breakdowns are maintained in the supporting documentation and are available on request.

15. Late-Breaking Information

No late-breaking safety information became available between the DLP and the finalisation of this report that would materially affect the safety assessment or the benefit-risk conclusions. No new significant safety finding, no action taken for safety reasons, and no relevant regulatory development occurred in the interim.

16. Overall Safety Assessment

16.1 Evaluation of the Risks

The cumulative safety data for TILA-278 — approximately 671 subjects exposed to active treatment and approximately 140 patient-years of exposure, with the pivotal study contributing 599 actively treated subjects over a 12-week induction period — provide a robust characterisation of the short-term safety profile of subcutaneous TILA-278 in adults with moderate-to-severe UC. The evaluation of the important risks is as follows:

• Injection-site reactions (important identified risk). The principal drug-attributable finding, reported more frequently on active SC treatment than on placebo and without a dose-dependent gradient between the High and Low arms. Events were predominantly mild-to-moderate, transient, and local, and did not lead to a meaningful excess of treatment discontinuation. This is a well-understood, largely manageable local effect intrinsic to SC biologic administration.
• Serious and opportunistic infections (important potential risk). TL1A antagonism dampens TH1/TH17 immunity, creating a mechanistically plausible potential for serious bacterial, viral, fungal, and opportunistic infection, including reactivation of latent tuberculosis or hepatitis B, particularly in a population commonly exposed to concomitant corticosteroids/immunomodulators. No excess of serious infection was observed over the 12-week induction period, but the short exposure and the size of the current database preclude exclusion of a longer-term, class-consistent risk. The risk is mitigated in part through pre-treatment screening (tuberculosis, hepatitis B/C), vaccination review, and physician/patient awareness.
• Malignancy, including epithelial/colorectal neoplasia (important potential risk). Two strands support this potential risk: the general consideration of chronic immunomodulation in immune-mediated inflammatory disease; and, specific to this molecule, IL-22 receptor agonism, which promotes the epithelial proliferation that drives mucosal healing and warrants specific long-term vigilance for epithelial/colorectal neoplasia in a UC population already at elevated background colorectal-cancer risk. No malignancy signal was identified over the induction period, but latency and exposure duration make this an inherently long-term question.
• Immunogenicity (important potential risk). As a humanised bispecific IgG1, TILA-278 can elicit ADA, including neutralising antibodies, with potential to reduce exposure and efficacy or, less commonly, to contribute to hypersensitivity or administration reactions. Immunogenicity is assessed with a validated tiered assay with characterisation of the impact of ADA on PK, efficacy, and safety. Observed ADA incidence over induction was low and without a clear clinical impact on remission rates or safety; durable, repeat-dosing data are needed to characterise incidence, persistence, and neutralising potential.
• Long-term safety and use in pregnancy and breast-feeding (missing information). Controlled experience is limited to a 12-week induction period in adults; long-term safety and use in pregnancy and lactation (relevant given placental transfer of IgG1 predominantly in the second and third trimesters via FcRn) remain to be characterised.

No dose-dependent safety signal was identified, serious events were numerically fewer in the combined active arms than on placebo, no serious adverse reaction or SUSAR was reported, and there was no hepatic, renal, or haematological toxicity signal. The overall short-term safety profile is consistent with the anti-TL1A/IL-22 mechanism and with the established biologic class.

16.2 Benefit-Risk Considerations

The benefit of TILA-278 in moderate-to-severe UC is well demonstrated for the induction setting: a large, statistically significant, dose-ordered effect on Week 12 clinical remission (37.3% High and 16.2% Low versus 0.7% placebo), supported by a substantial LS-mean reduction in modified Mayo score (differences versus placebo of −2.36 and −1.77, both p < 0.0001) and by endoscopic improvement (48.9%, 27.9%, and 6.2%). These benefits are set against a favourable short-term safety profile in which injection-site reactions were the principal drug-attributable finding and no dose-dependent safety signal was observed. On the basis of the clear efficacy signal and the favourable and well-characterised safety profile, the benefit-risk balance of TILA-278 in moderate-to-severe UC is positive, subject to confirmation of long-term safety through the planned pharmacovigilance activities.

17. Summary of Important Risks

Table 17-1. Summary of important risks and missing information

Category	Safety concern(s)
Important identified risks	Injection-site reactions
Important potential risks	Serious and opportunistic infections; malignancy (including epithelial/colorectal neoplasia); immunogenicity with potential impact on efficacy or safety
Missing information	Long-term safety (beyond 12-week induction exposure); use in pregnancy and breast-feeding

These concerns are managed by routine risk minimisation (product information, labelling, and restriction to prescription and administration under the supervision of a physician experienced in the management of UC) and, for serious infection, by an additional Patient Alert Card. Beyond routine pharmacovigilance (including targeted follow-up questionnaires for serious infection, malignancy, hypersensitivity/immunogenicity, and pregnancy exposure), the sponsor will conduct the long-term maintenance/extension study TILA278-301, a registry-based post-authorisation safety study focused on serious infection and malignancy, enhanced pregnancy-outcome surveillance, and ongoing immunogenicity characterisation.

18. Conclusions

During this reporting interval, the TILA-278 development programme completed the pivotal Phase 2b induction study TILA278-201, which met its primary endpoint with a large, dose-ordered effect on clinical remission and a favourable, well-characterised short-term safety profile. Across the cumulative development experience (approximately 671 subjects exposed to active TILA-278 and approximately 140 patient-years of exposure), no action was taken for safety reasons, no serious adverse reaction or SUSAR was reported, all deaths were assessed as unrelated to study treatment, and no dose-dependent safety signal or new safety concern emerged from the clinical, non-clinical, or literature review. The important risks and missing information remain as previously characterised: injection-site reactions (identified); serious and opportunistic infections, malignancy, and immunogenicity (potential); and long-term safety and use in pregnancy and breast-feeding (missing information). The benefit-risk balance of TILA-278 in moderate-to-severe UC remains positive. The sponsor concludes that no change to the ongoing conduct of the development programme is warranted for safety reasons and that continued development — including initiation of the long-term maintenance and open-label extension study TILA278-301 to characterise long-term safety, immunogenicity, and durability of effect — is supported.

Appendices

• Appendix 1 — Investigator's Brochure for TILA-278 (current edition), including the Reference Safety Information (list of expected serious adverse reactions).
• Appendix 2 — Cumulative summary tabulations of serious adverse events by System Organ Class and Preferred Term (MedDRA version 28.1).
• Appendix 3 — Line listings of serious adverse events for the reporting interval (subject-level).
• Appendix 4 — Tabular inventory of clinical trials in the development programme (cross-reference to Module 5.2).
• Appendix 5 — Cumulative subject-exposure tabulations, including demographic distribution.
• Appendix 6 — Summary of the important risks and the pharmacovigilance/risk-minimisation activities (cross-reference to the Risk Management Plan).