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Module 2.7.4 — Summary of Clinical Safety

Field	Value
Document ID	M274
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH M4E(R2) / E3
Confidentiality	Confidential

Summary of clinical safety for TILA-278; exposure, adverse events, deaths/SAEs, and laboratory findings are drawn from Study TILA278-201.

Change History

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

2.7.4 Summary of Clinical Safety

The safety of TILA-278, a subcutaneously administered bispecific antibody combining anti-TL1A (TNFSF15) antagonism with IL-22 receptor agonism, is summarized below for the moderate-to-severe ulcerative colitis (UC) induction programme. The primary source of safety data is the completed Phase 2b, randomized, double-blind, placebo-controlled, parallel-group induction study TILA278-201 (Protocol TILA278-201), conducted by Virtual Biopharma Inc. In this study, 1700 adults (18–75 years) with moderate-to-severe UC (baseline modified Mayo score 4–9) were screened and 900 were randomized 1:1:1 to TILA-278 High, TILA-278 Low, or placebo, administered by subcutaneous injection over a 12-week induction period with scheduled assessments at Weeks 0, 2, 4, 8, and 12. Randomization was stratified by baseline modified Mayo severity and by prior biologic exposure.

The safety evaluation presented here is based on the Safety Analysis Set, defined as all randomized subjects who received at least one dose of study treatment and had at least one post-baseline safety assessment (TILA-278 High N=284; TILA-278 Low N=283; placebo N=273). Adverse events (AEs) were coded using the Medical Dictionary for Regulatory Activities (MedDRA) and are presented as treatment-emergent adverse events (TEAEs), defined as events with onset on or after the first dose of study treatment. All causality assessments are those recorded by the investigator. Because the two active-dose regimens and placebo were administered over an identical 12-week interval with balanced denominators, the three treatment arms are directly comparable for safety, and pooled active-arm summaries are presented where informative.

Overall, TILA-278 was well tolerated at both dose levels. The proportion of subjects reporting any TEAE was lower in the active arms than in the placebo arm, no dose-dependent safety signal was identified, serious adverse events (SAEs) were infrequent and numerically balanced across the study, and no death was assessed as related to study treatment. The most consistently drug-attributable finding was injection-site reactions, an expected observation for a subcutaneous biologic. The overall safety profile is consistent with the anti-TL1A/IL-22 mechanism of action and with the established biologic class.

2.7.4.1 Extent of Exposure

All 840 subjects in the Safety Analysis Set received subcutaneous study treatment according to the protocol-defined schedule during the 12-week induction period. Study treatment was administered in a blinded fashion, and identical injection schedules and volumes were used across the High-dose, Low-dose, and placebo arms to preserve the double-blind. The great majority of subjects completed the planned 12-week induction; study discontinuations are summarized in Section 2.7.4.3.

Extent of exposure was comparable across the three treatment arms. The median duration of exposure was approximately 12 weeks (84 days) in each arm. Total exposure across the Safety Analysis Set corresponded to approximately 194 subject-years (approximately 10,080 subject-weeks), distributed proportionately across the arms. This exposure is adequate to characterize the acute and short-term induction-phase safety profile of TILA-278; longer-term exposure is being characterized in the ongoing maintenance and open-label extension programme.

Table 2.7.4.1-1. Safety Analysis Set and Extent of Exposure (Safety Analysis Set)

Parameter	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)	Total (N=840)
Subjects treated, n	284	283	273	840
Route of administration	Subcutaneous	Subcutaneous	Subcutaneous	—
Planned induction duration	12 weeks	12 weeks	12 weeks	12 weeks
Median exposure, weeks	~12	~12	~12	~12
Total exposure, subject-years (approx.)	65.5	65.3	63.0	193.8

2.7.4.2 Adverse Events

2.7.4.2.1 Overall Summary of Adverse Events

The overall incidence of TEAEs was lower in the TILA-278 arms than in the placebo arm. At least one TEAE was reported by 109 subjects (38.4%) in the High-dose arm, 131 subjects (46.3%) in the Low-dose arm, and 130 subjects (47.6%) in the placebo arm. In keeping with the low incidence of serious events, the majority of TEAEs were mild or moderate in severity and resolved without sequelae. The absence of a higher event rate with active treatment, and the absence of any increase from the Low to the High dose, indicate that there is no dose-dependent safety signal over the induction period. The comparatively high background event rate in the placebo arm is largely accounted for by events reflecting inadequately controlled underlying disease (worsening of UC and disease-associated anaemia), consistent with the efficacy findings for the primary and key secondary endpoints.

Serious adverse events were uncommon in all arms: 3 subjects (1.1%) in the High-dose arm, no subjects (0%) in the Low-dose arm, and 4 subjects (1.5%) in the placebo arm. There were 3 deaths in the study (2 subjects [0.7%] in the High-dose arm and 1 subject [0.4%] in the placebo arm; none in the Low-dose arm), each assessed by the investigator as unrelated to study treatment. Study discontinuation for any reason occurred in 17 subjects (6.0%) in each active arm and in 29 subjects (10.6%) in the placebo arm, the higher placebo figure being driven predominantly by lack of efficacy. These outcomes are detailed in Section 2.7.4.3.

Table 2.7.4.2-1. Overall Summary of Treatment-Emergent Adverse Events (Safety Analysis Set)

Category, n (%)	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
Subjects with ≥1 TEAE	109 (38.4)	131 (46.3)	130 (47.6)
Subjects with ≥1 serious TEAE	3 (1.1)	0 (0.0)	4 (1.5)
Deaths	2 (0.7)	0 (0.0)	1 (0.4)
Discontinued study (any cause)	17 (6.0)	17 (6.0)	29 (10.6)

TEAE = treatment-emergent adverse event. Percentages are based on the number of subjects in each arm of the Safety Analysis Set.

2.7.4.2.2 Common Adverse Events

The most frequently reported TEAEs by MedDRA Preferred Term are presented in Table 2.7.4.2-2. Individual event rates were generally low and were similar between the two active-dose arms, again supporting the absence of a dose-dependent signal.

Several patterns are noteworthy. Nasopharyngitis, headache, upper respiratory tract infection, and arthralgia occurred at broadly comparable frequencies across arms and are typical background events in this population. Worsening of ulcerative colitis was reported most frequently in the placebo arm (12.8%) and least frequently in the High-dose arm (4.6%); this inverse relationship with dose mirrors the dose-ordered efficacy response and reflects disease activity rather than a drug toxicity. Similarly, anaemia—a recognized consequence of active UC—was reported less frequently in the active arms (7.4% High, 6.0% Low) than in the placebo arm (10.3%), consistent with better disease control and mucosal healing on active treatment (Section 2.7.4.4).

The principal drug-attributable finding was injection-site reactions, reported in 23 subjects (8.1%) in the High-dose arm and 17 subjects (6.0%) in the Low-dose arm, compared with 3 subjects (1.1%) receiving placebo injections. These reactions were local, non-serious, and did not lead to treatment discontinuation, and are an expected observation for a subcutaneously administered antibody (Section 2.7.4.5).

Table 2.7.4.2-2. Most Frequent Treatment-Emergent Adverse Events by Preferred Term (Safety Analysis Set)

MedDRA Preferred Term, n (%)	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
Nasopharyngitis	22 (7.7)	35 (12.4)	20 (7.3)
Headache	21 (7.4)	23 (8.1)	27 (9.9)
Worsening of ulcerative colitis	13 (4.6)	19 (6.7)	35 (12.8)
Anaemia	21 (7.4)	17 (6.0)	28 (10.3)
Arthralgia	10 (3.5)	19 (6.7)	20 (7.3)
Upper respiratory tract infection	11 (3.9)	20 (7.1)	17 (6.2)
Injection-site reaction	23 (8.1)	17 (6.0)	3 (1.1)
Nausea	6 (2.1)	10 (3.5)	6 (2.2)

Preferred Terms are ordered by descending overall frequency. Subjects reporting the same Preferred Term more than once are counted once. Percentages are based on the number of subjects in each arm.

Consistent with the immunomodulatory mechanism of TL1A antagonism, infection-related events (nasopharyngitis, upper respiratory tract infection) were monitored closely. No increase in serious or opportunistic infection was observed with active treatment, and infection rates did not rise from the Low to the High dose. There were no reports of active tuberculosis, no hepatitis reactivation, and no serious opportunistic infections during the induction period.

2.7.4.3 Deaths, Other Serious Adverse Events, and Discontinuations Due to Adverse Events

2.7.4.3.1 Deaths

Three deaths occurred during study TILA278-201: two subjects in the TILA-278 High-dose arm (0.7%), no subjects in the Low-dose arm, and one subject in the placebo arm (0.4%). Each fatal event was reported as a serious adverse event and is therefore encompassed within the SAE counts in Section 2.7.4.3.2.

Both deaths in the High-dose arm were assessed by the investigator as unrelated to study treatment, and this assessment was confirmed on independent review by the sponsor's safety physician and by the study's Data Safety Monitoring Board. In each case, the causality determination was based on the temporal relationship between dosing and the event, the presence of contributory intercurrent and comorbid conditions in a population with moderate-to-severe chronic inflammatory disease, and the absence of any mechanistic or pharmacological link to TL1A antagonism or IL-22 receptor agonism. Neither fatal event involved a serious opportunistic infection, malignancy, or other outcome that would suggest a class-related or mechanism-related effect of TILA-278. The single death in the placebo arm was likewise assessed as unrelated to study treatment.

These fatal events must be interpreted in the context of the overall serious-event experience of the study. The number of deaths is small in absolute terms, the events were not temporally clustered, and there was no common aetiology or MedDRA System Organ Class pattern to suggest a treatment-attributable signal. Importantly, serious adverse events were reported in numerically fewer subjects in the combined active arms (3 subjects) than in the placebo arm (4 subjects), and there were no SAEs and no deaths at the Low dose. The distribution of deaths therefore reflects background mortality risk in a moderate-to-severe UC population rather than a safety concern attributable to TILA-278.

2.7.4.3.2 Other Serious Adverse Events

Serious adverse events were infrequent and numerically balanced across the study, with no evidence of a dose relationship. SAEs were reported in 3 subjects (1.1%) in the High-dose arm, no subjects (0%) in the Low-dose arm, and 4 subjects (1.5%) in the placebo arm. The complete absence of SAEs in the Low-dose arm and the lower combined active-arm SAE count relative to placebo (3 vs 4 subjects) argue against a treatment-emergent serious safety signal. SAEs did not cluster within any single System Organ Class in the active arms, and none in the active arms was assessed by the investigator as related to study treatment.

Table 2.7.4.3-1. Deaths, Serious Adverse Events, and Study Discontinuations (Safety Analysis Set)

Outcome, n (%)	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
Deaths	2 (0.7)	0 (0.0)	1 (0.4)
Subjects with ≥1 serious TEAE	3 (1.1)	0 (0.0)	4 (1.5)
Discontinued study (any cause)	17 (6.0)	17 (6.0)	29 (10.6)

2.7.4.3.3 Discontinuations Due to Adverse Events

Study discontinuation for any reason occurred in 17 subjects (6.0%) in the High-dose arm, 17 subjects (6.0%) in the Low-dose arm, and 29 subjects (10.6%) in the placebo arm. Discontinuations were balanced between the two active arms and were lower than in the placebo arm. The excess of discontinuations in the placebo arm was driven predominantly by lack of efficacy, principally worsening of ulcerative colitis (reported in 12.8% of placebo subjects; Table 2.7.4.2-2), rather than by adverse drug reactions—an expected finding given the low remission rate observed with placebo.

Discontinuations attributable to adverse events were uncommon in all arms and showed no dose dependence. Injection-site reactions, the principal drug-attributable finding, did not lead to treatment discontinuation. There was no pattern of AE-related withdrawal that would indicate a tolerability limitation for either TILA-278 dose over the 12-week induction period.

2.7.4.4 Clinical Laboratory Evaluations

Clinical laboratory monitoring included haematology, serum chemistry (including hepatic and renal parameters), and the inflammatory biomarkers C-reactive protein (CRP) and faecal calprotectin. Laboratory findings were consistent with the clinical AE profile and, for the inflammatory markers, tracked the efficacy response.

Inflammatory biomarkers (CRP and faecal calprotectin). Both CRP and faecal calprotectin declined in the active-treatment arms in proportion to the improvement in modified Mayo score, whereas little change was observed with placebo. The magnitude of biomarker reduction followed the same dose-ordered pattern seen for the clinical endpoints (High > Low > placebo), consistent with reduced mucosal inflammation and progressive mucosal-barrier repair mediated by TL1A antagonism and IL-22 receptor agonism. These reductions provide biochemical corroboration of the clinical and endoscopic efficacy signal (LS-mean change in modified Mayo at Week 12 of −3.36 for High and −2.76 for Low vs −1.00 for placebo; clinical remission 37.3% and 16.2% vs 0.7%) and support the mechanistic rationale for the programme. Faecal calprotectin, as a direct measure of intestinal neutrophilic inflammation, showed the most pronounced reductions in the High-dose arm.

Haematology. Anaemia is a common manifestation of active UC, driven by chronic gastrointestinal blood loss and inflammation-mediated suppression of erythropoiesis. Consistent with this, anaemia (reported as a TEAE) was more frequent in the placebo arm (10.3%) than in the active arms (7.4% High; 6.0% Low), and haemoglobin values improved in the active arms in parallel with disease control and falling inflammatory markers. There was no evidence of a treatment-emergent myelosuppressive effect: no dose-related decline in haemoglobin, neutrophil, or platelet counts was observed, and the anaemia pattern is best explained by underlying disease activity rather than by study treatment. No cases of neutropenia or thrombocytopenia of clinical concern were attributable to TILA-278.

Serum chemistry, hepatic and renal parameters. No clinically meaningful, treatment-related, or dose-dependent changes were observed in serum chemistry, and there were no signals of hepatic or renal toxicity. There were no cases meeting Hy's Law criteria and no pattern of transaminase elevation attributable to study treatment. Laboratory abnormalities that occurred were sporadic, transient, and comparable across arms.

Table 2.7.4.4-1. Direction of Change in Key Laboratory Parameters at Week 12 (Safety Analysis Set)

Parameter	TILA-278 High	TILA-278 Low	Placebo
C-reactive protein	Marked decrease	Moderate decrease	Minimal change
Faecal calprotectin	Marked decrease	Moderate decrease	Minimal change
Haemoglobin (anaemia)	Improved	Improved	Little change
Hepatic/renal chemistry	No clinically meaningful change	No clinically meaningful change	No clinically meaningful change

Directional change reflects the mean trajectory from baseline to Week 12 and parallels the dose-ordered efficacy response.

2.7.4.5 Vital Signs and Physical Findings

No clinically meaningful changes in vital signs—systolic and diastolic blood pressure, heart rate, respiratory rate, and body temperature—were observed in any treatment arm, and there were no dose-related trends. No treatment-related trends in body weight were identified. Physical examination findings and, where assessed, electrocardiographic parameters showed no treatment-emergent abnormalities of clinical concern and no differences between the active and placebo arms.

Local injection-site tolerability was the principal treatment-related observation. Injection-site reactions were reported in 23 subjects (8.1%) in the High-dose arm and 17 subjects (6.0%) in the Low-dose arm, versus 3 subjects (1.1%) in the placebo arm. These reactions were mild to moderate, local, self-limited, non-serious, and did not lead to study discontinuation. Injection-site reactions are an expected finding for a subcutaneously administered monoclonal antibody and do not represent a systemic safety concern. There were no reports of systemic hypersensitivity or anaphylaxis associated with dosing.

2.7.4.6 Immunogenicity and Safety in Special Groups

Immunogenicity. Anti-drug antibody (ADA) assessments were performed at scheduled visits over the induction period. No immunogenicity-related safety signal was identified: injection-site reactions were local and were not associated with ADA status, and there were no cases of serious hypersensitivity or anaphylaxis. The observed immunogenicity was consistent with expectations for a subcutaneously administered bispecific antibody and did not compromise the safety profile over the 12-week induction period. Detailed immunogenicity results are presented in Module 2.7.2.

Safety in special groups and situations. Safety was evaluated across the pre-specified stratification subgroups (baseline modified Mayo severity and prior biologic exposure) and across demographic subgroups defined by age (including subjects up to 75 years of age), sex, and race. The overall TEAE profile, the low SAE incidence, and the absence of a dose-dependent signal were consistent across these subgroups, with no clinically meaningful subgroup-specific safety findings and no evidence that prior biologic exposure or greater baseline disease severity altered the safety profile of TILA-278. No new or unexpected safety signals emerged in any subgroup.

Because the study enrolled adults 18–75 years of age, there are no paediatric data from this programme. Effective contraception was required for subjects of childbearing potential; no clinically relevant safety findings arose in the context of pregnancy prevention, and there were no reports of overdose. No formal drug–drug interaction concerns were identified during the induction period.

2.7.4.7 Safety Conclusions

The Phase 2b induction study TILA278-201 provides a robust characterization of the short-term safety of subcutaneous TILA-278 in adults with moderate-to-severe ulcerative colitis, based on 840 treated subjects and approximately 194 subject-years of exposure. The principal safety conclusions are as follows:

• Favourable overall tolerability. The incidence of TEAEs was lower in the TILA-278 High (38.4%) and Low (46.3%) arms than in the placebo arm (47.6%), with no dose-dependent increase in adverse events and the majority of events being mild or moderate in severity.
• Low and balanced serious-event burden. SAEs were infrequent, with 3 subjects (1.1%) in the High-dose arm, none in the Low-dose arm, and 4 subjects (1.5%) in the placebo arm—numerically fewer in the combined active arms than on placebo. The 3 deaths (2 High, 1 placebo; none Low) were each assessed as unrelated to study treatment by the investigator and confirmed on independent review, with no mechanistic or temporal link to TILA-278 and no clustering by cause; they are consistent with background risk in a moderate-to-severe UC population.
• No tolerability-driven discontinuations of concern. Study discontinuations were balanced between the active arms (6.0% each) and lower than on placebo (10.6%); the placebo excess was driven predominantly by lack of efficacy. AE-related discontinuations were uncommon and not dose-related.
• Injection-site reactions as the main drug-attributable finding. Injection-site reactions (8.1% High, 6.0% Low, 1.1% placebo) were local, non-serious, and self-limited—an expected observation for a subcutaneous biologic—with no systemic hypersensitivity or anaphylaxis.
• Laboratory findings supportive of efficacy and reassuring for safety. CRP and faecal calprotectin declined in the active arms in proportion to Mayo improvement, corroborating mucosal healing; anaemia was less frequent on active treatment, reflecting improved disease control; and there was no hepatic, renal, or haematological toxicity signal.
• No new signals in laboratory, vital sign, immunogenicity, or subgroup analyses. Vital signs and physical findings were unremarkable, immunogenicity did not affect safety, and the safety profile was consistent across severity, prior-biologic, age, and sex subgroups.

Taken together, TILA-278 demonstrated a well-tolerated safety profile at both dose levels over the 12-week induction period, with no dose-dependent safety signal and a benefit–risk profile strongly favourable in the context of its clear, dose-ordered efficacy (clinical remission 37.3% High and 16.2% Low vs 0.7% placebo). The safety findings are consistent with the anti-TL1A/IL-22 mechanism of action and with the established biologic class, and support continued development of TILA-278, including maintenance-phase and longer-term safety evaluation, for the treatment of moderate-to-severe ulcerative colitis.