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Module 2.7.3 — Summary of Clinical Efficacy

Field	Value
Document ID	M273
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH M4E(R2) / E3
Confidentiality	Confidential

Summary of clinical efficacy for TILA-278; the Week-12 induction results (modified Mayo change and clinical remission) are drawn from Study TILA278-201.

Change History

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

2.7.3 Summary of Clinical Efficacy

2.7.3.1 Background and Overview of Clinical Efficacy

2.7.3.1.1 Disease Background and Unmet Medical Need

Ulcerative colitis (UC) is a chronic, relapsing–remitting inflammatory disease of the colonic mucosa characterized by rectal bleeding, urgency, increased stool frequency, and progressive mucosal injury. Moderately-to-severely active disease is associated with substantial morbidity, impaired quality of life, corticosteroid dependency, hospitalization, and colectomy. Although several biologic and small-molecule therapies are approved for moderate-to-severe UC, a substantial proportion of patients fail to achieve clinical remission with induction therapy, lose response over time, or discontinue owing to intolerance. The need for induction agents that combine potent control of mucosal inflammation with active restoration of the epithelial barrier — including in patients with prior biologic exposure — remains incompletely met.

2.7.3.1.2 Mechanistic Rationale

TILA-278 is a subcutaneously administered bispecific antibody that simultaneously antagonizes TL1A (TNFSF15) and agonizes the IL-22 pathway. TL1A antagonism attenuates TH1/TH17-driven mucosal inflammation and the pro-fibrotic signaling that contributes to intestinal tissue remodeling, while IL-22R agonism promotes intestinal epithelial regeneration and mucosal-barrier repair. These two mechanisms are complementary: suppression of the inflammatory drivers of active colitis is combined with active promotion of mucosal healing. This dual mechanism provides a coherent biological rationale for an induction effect that couples symptomatic improvement with objective endoscopic healing, and for a favorable benefit–risk profile consistent with the anti-TL1A/IL-22 biologic class.

2.7.3.1.3 Overview of the Clinical Efficacy Program

The clinical efficacy of TILA-278 in moderate-to-severe UC is established by Study TILA278-201, a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group induction study conducted by Virtual Biopharma Inc. The study evaluated two subcutaneous dose regimens of TILA-278 (High and Low) against placebo over a 12-week induction period, with the primary objective of demonstrating superiority over placebo for the induction of clinical remission at Week 12. This Summary of Clinical Efficacy summarizes the efficacy findings of Study TILA278-201, which constitute the primary evidence of efficacy for the induction indication; the corresponding safety data are presented in Module 2.7.4 (Summary of Clinical Safety).

The primary efficacy endpoint was clinical remission at Week 12, defined as a modified Mayo score ≤ 2 with no individual subscore > 1. Key secondary endpoints were change from baseline in the modified Mayo score at Week 12 and endoscopic improvement at Week 12. Endpoints were assessed using centrally read endoscopy and standardized clinical assessment. Both TILA-278 dose regimens demonstrated statistically significant and clinically meaningful superiority over placebo on the primary and key secondary endpoints, with a clear dose-ordered response.

2.7.3.2 Summary of Results of Individual Studies

2.7.3.2.1 Study TILA278-201 — Design

Study TILA278-201 was a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group induction study in adults aged 18–75 years with moderately-to-severely active UC (baseline modified Mayo score 4–9). A total of 1700 subjects were screened and 900 were randomized 1:1:1 to receive TILA-278 High, TILA-278 Low, or placebo administered subcutaneously over a 12-week induction period, with study visits at Weeks 0, 2, 4, 8, and 12. Randomization was stratified by baseline modified Mayo severity and prior biologic exposure to ensure balanced allocation of these key prognostic factors across treatment arms.

The primary endpoint was clinical remission (modified Mayo ≤ 2, with no individual subscore > 1) at Week 12. Key secondary endpoints were change from baseline in the modified Mayo score at Week 12 and endoscopic improvement at Week 12.

2.7.3.2.2 Analysis Sets and Subject Disposition

The Full Analysis Set (FAS) comprised all randomized subjects with a baseline and at least one post-baseline efficacy assessment and served as the primary population for efficacy analyses. Randomized and FAS numbers by treatment group are summarized in Table 2.7.3-1.

Table 2.7.3-1. Subject Disposition and Analysis Sets (Study TILA278-201)

Disposition	TILA-278 High	TILA-278 Low	Placebo	Total
Screened	—	—	—	1700
Randomized	299	300	301	900
Full Analysis Set (FAS)	284	283	273	840
Discontinued study	17	17	29	63

Discontinuations were more frequent in the placebo group (29 subjects) than in either active arm (17 subjects each), driven mainly by lack of efficacy in the placebo group. The FAS was well balanced across treatment arms, and the stratified randomization achieved comparable distributions of baseline modified Mayo severity and prior biologic exposure across groups.

2.7.3.2.3 Primary Endpoint — Clinical Remission at Week 12

At Week 12, clinical remission was achieved by 37.3% (106/284) of subjects in the TILA-278 High group and 16.2% (46/283) in the TILA-278 Low group, compared with 0.7% (2/273) in the placebo group. The risk difference versus placebo was +36.6 percentage points (95% CI 30.9 to 42.3; p < 0.0001) for the High dose and +15.5 percentage points (95% CI 11.1 to 19.9; p < 0.0001) for the Low dose. Both dose regimens were statistically superior to placebo, with a clear dose-ordered response (High > Low > Placebo).

2.7.3.2.4 Key Secondary Endpoint — Change from Baseline in Modified Mayo Score at Week 12

Based on an ANCOVA of change from baseline (covariates: treatment and baseline modified Mayo score), the LS-mean change in modified Mayo score at Week 12 was −3.36 for TILA-278 High, −2.76 for TILA-278 Low, and −1.00 for placebo. The LS-mean difference versus placebo was −2.36 (95% CI −2.49 to −2.23; p < 0.0001) for the High dose and −1.77 (95% CI −1.90 to −1.64; p < 0.0001) for the Low dose. The magnitude of Mayo reduction paralleled the remission findings and reinforced the dose-ordered treatment effect.

2.7.3.2.5 Key Secondary Endpoint — Endoscopic Improvement at Week 12

Endoscopic improvement at Week 12 (centrally read Mayo endoscopic subscore ≤ 1) was achieved by 48.9% (139/284) of TILA-278 High subjects and 27.9% (79/283) of TILA-278 Low subjects, compared with 6.2% (17/273) of placebo subjects (High vs placebo +42.7 percentage points, Low vs placebo +21.7 percentage points; both p < 0.0001). The objective endoscopic benefit is consistent with the IL-22–driven mucosal-healing component of the TILA-278 mechanism and supports the primary and Mayo-change findings.

2.7.3.2.6 Supportive Biomarker Findings

Inflammatory markers declined in the active arms in proportion to the improvement in modified Mayo score. C-reactive protein (CRP) and faecal calprotectin decreased in the TILA-278 High and Low groups relative to placebo, with the greatest reductions observed in the High-dose group. The concordance between symptomatic improvement, endoscopic healing, and objective biomarker reduction provides internally consistent, multi-domain evidence of an anti-inflammatory and mucosal-healing induction effect.

2.7.3.3 Comparison and Analyses of Results Across Studies

The efficacy of TILA-278 for the induction indication is established by the single, adequately powered, placebo-controlled Study TILA278-201. Accordingly, the analyses below present the primary and key secondary efficacy results from that study, which constitute the integrated evidence of efficacy. Because both dose regimens were evaluated concurrently within a single randomized, double-blind study, direct within-study comparisons are unconfounded by cross-study heterogeneity in population, design, or endpoint definition.

2.7.3.3.1 Primary Endpoint — Clinical Remission at Week 12

Both TILA-278 dose regimens were statistically significantly superior to placebo for the induction of clinical remission at Week 12. Results are summarized in Table 2.7.3-2.

Table 2.7.3-2. Clinical Remission at Week 12 (Modified Mayo ≤ 2, no subscore > 1; FAS)

Treatment	Remitters, n/N	Remission rate, %	Risk difference vs placebo, percentage points (95% CI)	p-value
TILA-278 High	106/284	37.3	+36.6 (30.9 to 42.3)	< 0.0001
TILA-278 Low	46/283	16.2	+15.5 (11.1 to 19.9)	< 0.0001
Placebo	2/273	0.7	— (reference)	—

The near-absent placebo remission rate (0.7%) is consistent with the stringent composite remission definition and the moderate-to-severe baseline population, and it underscores the magnitude of the treatment effect. The absolute remission benefit of the High dose (+36.6 percentage points) and the clear separation of the Low dose from placebo (+15.5 percentage points) both exceed thresholds generally regarded as clinically meaningful for UC induction.

2.7.3.3.2 Key Secondary Endpoint — Change from Baseline in Modified Mayo Score at Week 12 (ANCOVA)

The ANCOVA analysis of change from baseline in the modified Mayo score at Week 12 is presented in Table 2.7.3-3. Both dose regimens produced statistically significant reductions relative to placebo, with a monotonic dose-ordered effect.

Table 2.7.3-3. ANCOVA of Change from Baseline in Modified Mayo Score at Week 12 (FAS; covariates: treatment, baseline score)

Treatment	N	LS-mean change from baseline (SE)	LS-mean difference vs placebo (95% CI)	p-value
TILA-278 High	284	−3.36 (0.05)	−2.36 (−2.49 to −2.23)	< 0.0001
TILA-278 Low	283	−2.76 (0.05)	−1.77 (−1.90 to −1.64)	< 0.0001
Placebo	273	−1.00 (0.05)	— (reference)	—

The tight confidence intervals around the treatment differences reflect the size and precision of the study and the consistency of the effect. The rank ordering of LS-mean reductions (High −3.36 > Low −2.76 > Placebo −1.00) mirrors the remission results and provides concordant, continuous-endpoint confirmation of the dichotomous primary outcome.

2.7.3.3.3 Consistency Across Endpoints

Across the primary endpoint (clinical remission), the key secondary continuous endpoint (modified Mayo change), the objective endoscopic endpoint (endoscopic improvement), and supportive biomarkers (CRP, faecal calprotectin), the direction, rank ordering, and statistical significance of the treatment effect were concordant. This multi-domain consistency — symptomatic, endoscopic, and biochemical — strengthens the conclusion that the observed benefit reflects a genuine disease-modifying induction effect rather than an isolated finding on a single measure.

2.7.3.4 Analysis of Clinical Information Relevant to Dosing Recommendations

2.7.3.4.1 Dose–Response Relationship

Study TILA278-201 evaluated two subcutaneous dose regimens against placebo and demonstrated a clear, monotonic dose-ordered response across all efficacy domains. For the primary endpoint, remission rates increased from 0.7% (placebo) to 16.2% (Low) to 37.3% (High). For the key secondary continuous endpoint, LS-mean Mayo reductions increased in the same order (−1.00, −2.76, −3.36), as did endoscopic improvement (6.2%, 27.9%, 48.9%). The consistency of the dose ordering across independent endpoints supports a true exposure–response relationship rather than chance separation.

Table 2.7.3-4. Dose-Ordered Efficacy Response at Week 12 (FAS)

Endpoint	Placebo	TILA-278 Low	TILA-278 High
Clinical remission, %	0.7	16.2	37.3
LS-mean change in modified Mayo	−1.00	−2.76	−3.36
Endoscopic improvement, %	6.2	27.9	48.9
Remission difference vs placebo, pp	—	+15.5	+36.6

2.7.3.4.2 Dose Selection

Both dose regimens achieved statistically significant and clinically meaningful superiority over placebo; however, the High dose provided a consistently greater treatment effect across every efficacy endpoint, approximately doubling the remission rate relative to the Low dose (37.3% vs 16.2%) and producing a larger reduction in the modified Mayo score (−3.36 vs −2.76). Importantly, the greater efficacy of the High dose was not accompanied by a dose-dependent safety signal: the frequency of treatment-emergent adverse events, serious adverse events, and discontinuations did not increase with dose, and injection-site reactions — the principal drug-attributable finding — did not show a dose-dependent pattern of concern (the safety profile is summarized in detail in Module 2.7.4, Summary of Clinical Safety). The favorable benefit–risk profile at the High dose, combined with the magnitude and consistency of its efficacy, supports selection of the TILA-278 High regimen as the recommended induction dose for further confirmatory evaluation, with the Low dose retained as a clinically active alternative.

2.7.3.5 Persistence of Efficacy Over the Induction Period

Efficacy was assessed longitudinally at Weeks 2, 4, 8, and 12. Both TILA-278 dose regimens produced early and progressive improvement in the modified Mayo score, with separation from placebo evident by the first post-baseline assessment (Week 2) and increasing progressively through Week 12. The trajectory of the LS-mean change from baseline is summarized in Table 2.7.3-5.

Table 2.7.3-5. LS-Mean Change from Baseline in Modified Mayo Score Over the Induction Period (FAS)

Visit	TILA-278 High	TILA-278 Low	Placebo	High − Placebo	Low − Placebo
Week 2	−1.10	−0.90	−0.45	−0.65	−0.45
Week 4	−1.95	−1.55	−0.68	−1.27	−0.87
Week 8	−2.80	−2.25	−0.88	−1.92	−1.37
Week 12	−3.36	−2.76	−1.00	−2.36	−1.77

Note: Between-group values are LS-mean differences versus placebo. The Week 12 estimates correspond to the primary ANCOVA analysis (Table 2.7.3-3); minor differences from the arithmetic difference of the rounded LS-means reflect rounding of the model-based estimates.

The improvement in modified Mayo score was progressive and sustained throughout the 12-week induction period, with no evidence of attenuation or of a plateau prior to Week 12. The dose-ordered separation between the High and Low regimens was maintained at every visit, and the magnitude of the treatment difference versus placebo increased monotonically over time. The early onset of effect (evident at Week 2) followed by continued deepening of response through Week 12 is consistent with the combined mechanism of TILA-278, in which rapid dampening of mucosal inflammation is followed by progressive IL-22–driven epithelial regeneration and mucosal-barrier repair. These findings support the adequacy of a 12-week induction period and indicate that efficacy persists and deepens across the full duration of induction.

2.7.3.6 Efficacy in Subpopulations

Prespecified subgroup analyses of the primary endpoint were conducted according to the randomization stratification factors: baseline modified Mayo severity and prior biologic exposure. The treatment effect of TILA-278 relative to placebo was consistent in direction and clinical relevance across all subgroups examined, with the dose-ordered response (High > Low > Placebo) preserved throughout.

2.7.3.6.1 Efficacy by Baseline Disease Severity

Clinical remission at Week 12 by baseline modified Mayo severity (moderate, 4–6; severe, 7–9) is summarized in Table 2.7.3-6. Remission rates were higher in subjects with moderate baseline disease than in those with severe disease across all treatment groups, consistent with the expected influence of baseline severity on outcome; however, the treatment benefit of TILA-278 versus placebo remained clinically meaningful in both severity strata.

Table 2.7.3-6. Clinical Remission at Week 12 by Baseline Modified Mayo Severity (FAS)

Subgroup	TILA-278 High, n/N (%)	TILA-278 Low, n/N (%)	Placebo, n/N (%)
Moderate (baseline Mayo 4–6)	76/170 (44.7)	34/169 (20.1)	2/163 (1.2)
Severe (baseline Mayo 7–9)	30/114 (26.3)	12/114 (10.5)	0/110 (0.0)

In both the moderate and severe strata, both TILA-278 doses achieved substantially higher remission rates than placebo, and the dose ordering (High > Low) was preserved. The retained efficacy in the severe stratum — where the placebo remission rate was 0.0% — is of particular clinical importance for this difficult-to-treat population.

2.7.3.6.2 Efficacy by Prior Biologic Exposure

Clinical remission at Week 12 by prior biologic status (biologic-naïve versus biologic-experienced) is summarized in Table 2.7.3-7. As anticipated, remission rates were higher in biologic-naïve subjects than in biologic-experienced subjects; nonetheless, both TILA-278 doses produced a clinically meaningful benefit over placebo in each subgroup.

Table 2.7.3-7. Clinical Remission at Week 12 by Prior Biologic Exposure (FAS)

Subgroup	TILA-278 High, n/N (%)	TILA-278 Low, n/N (%)	Placebo, n/N (%)
Biologic-naïve	68/156 (43.6)	30/155 (19.4)	2/150 (1.3)
Biologic-experienced	38/128 (29.7)	16/128 (12.5)	0/123 (0.0)

TILA-278 retained clinically meaningful efficacy in biologic-experienced subjects, a population that has typically responded less well to subsequent lines of therapy. In this subgroup, the High dose achieved a remission rate of 29.7% versus 0.0% for placebo, and the dose-ordered response was preserved. The maintenance of efficacy irrespective of prior biologic exposure is consistent with the distinct dual anti-TL1A/IL-22 mechanism of TILA-278, which does not rely on pathways targeted by conventional biologic therapies.

2.7.3.6.3 Consistency of Subgroup Findings

Across both stratification factors, the treatment effect of TILA-278 was consistent in direction and clinically relevant in magnitude, with no subgroup showing loss of benefit relative to placebo and the dose-ordered response preserved throughout. The consistency of efficacy across baseline severity and prior biologic status supports the generalizability of the overall induction results to the intended moderate-to-severe UC population, including patients with severe disease and those with prior biologic failure.