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

---

Phase 2 Study Synopsis (TILA-278)

Document ID: CSR-201
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E3

Supporting Study — Phase 2 Synopsis — TILA-278

Synopsis of the Phase 2 dose-ranging study of TILA-278 in Ulcerative Colitis (moderate-to-severe) — Protocol TILA278-201 — establishing the dose(s) and endpoints carried forward into the pivotal Phase 3 induction and maintenance programme. TILA-278 is a humanised, Chinese hamster ovary (CHO)-derived bispecific monoclonal antibody that simultaneously antagonises TL1A (TNFSF15) and agonises the IL-22 receptor, administered subcutaneously. This synopsis is presented in accordance with ICH E3 and summarises the design, conduct, and principal efficacy and safety findings of the double-blind 12-week induction study.

Administrative Information

Field	Value
Name of Sponsor/Company	Virtual Biopharma Inc.
Name of Finished Product	TILA-278 solution for subcutaneous injection, 150 mg/mL (300 mg per 2 mL single-use prefilled syringe)
Name of Active Ingredient	TILA-278, a humanised IgG1-based bispecific monoclonal antibody with anti-TL1A (TNFSF15) antagonist and IL-22 receptor agonist activity
Title of Study	A Phase 2b, Randomised, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of TILA-278 as Induction Therapy in Adults With Moderately to Severely Active Ulcerative Colitis
Protocol Number	TILA278-201
Development Phase	Phase 2b
Studied Period	First subject enrolled: 09 January 2024. Last subject last visit (Week 12): 04 March 2025.
Date of the Report	30 June 2026
Guideline Framework	ICH E3 (report); ICH E6(R2) (GCP); marketing application intended as a Biologics License Application under 21 CFR Part 601

Investigators and Study Centres

Multicentre study conducted at 142 investigational sites across 14 countries in North America, Europe, and the Asia-Pacific region. Sites were required to have qualified gastroenterology staff, endoscopic capability, and access to central endoscopy reading. The Coordinating Investigator and the complete list of participating principal investigators, together with their qualifications and site identifiers, are provided in Appendix 16.1.4.

Publication

None at the date of this report.

Product Description and Mechanistic Rationale

TILA-278 is a humanised IgG1-based bispecific monoclonal antibody produced by recombinant CHO cell culture and purified by a platform downstream process comprising Protein A affinity capture followed by orthogonal polishing chromatography and dedicated viral-clearance operations. The molecule integrates two independent, complementary mechanisms that address the distinct pathophysiological axes of ulcerative colitis:

• TL1A (TNFSF15) antagonism. One binding arm neutralises TL1A, blocking its engagement of death receptor 3 (DR3/TNFRSF25) on mucosal T cells and innate lymphoid cells. This attenuates the TH1/TH17-polarised inflammatory programme and the pro-fibrotic signalling implicated in tissue remodelling and stricturing, conferring anti-inflammatory and anti-fibrotic activity.
• IL-22 receptor agonism. The second arm engages the IL-22 receptor (the IL-22RA1/IL-10RB heterodimer) on intestinal epithelial cells, driving STAT3-dependent epithelial regeneration, antimicrobial peptide production, and mucus-barrier restoration — that is, active epithelial and mucosal healing.

The IgG1 backbone confers FcRn-mediated recycling and a prolonged serum half-life that supports an every-other-week subcutaneous induction schedule. The dual mechanism was hypothesised to combine suppression of the inflammatory drive with restoration of the epithelial barrier, thereby producing induction of remission superior to placebo in moderately to severely active UC. The finished product is formulated at 150 mg/mL for subcutaneous administration.

Nonclinical Context Supporting the Clinical Programme

The nonclinical programme was designed in accordance with ICH S6(R1) for biotechnology-derived pharmaceuticals. The cynomolgus monkey was the sole pharmacologically relevant species: TILA-278 binds cynomolgus TL1A and IL-22 receptor orthologues with affinities comparable to the human targets, whereas it lacks meaningful rodent cross-reactivity, rendering rodent models non-informative. GLP repeat-dose toxicology, toxicokinetics, and safety-pharmacology endpoints (cardiovascular, respiratory, and central nervous system parameters, incorporated into the repeat-dose design) were therefore characterised in cynomolgus monkeys.

Consistent with ICH S6(R1) and the nature of the molecule, standard genotoxicity and carcinogenicity studies were not conducted: a monoclonal antibody is not expected to interact with DNA or chromosomal targets, and no rodent bioassay is warranted absent a specific cause for concern. In vitro hERG assessment and a dedicated thorough QT study were likewise not warranted for a large-molecule biologic with no expectation of direct cardiac ion-channel interaction; cardiovascular safety was addressed within the primate toxicology studies. These positions informed the first-in-human and Phase 2b programmes and are documented in Module 2.4/2.6 and the nonclinical study reports.

Objectives

Primary objective. To evaluate the efficacy of TILA-278 compared with placebo in inducing clinical remission at Week 12 in adults with moderately to severely active ulcerative colitis.

Key secondary objectives. To evaluate the effect of TILA-278 versus placebo on (1) change from baseline in the modified Mayo score at Week 12 and (2) endoscopic improvement at Week 12.

Other objectives. To characterise the safety and tolerability of TILA-278; to assess the effect of TILA-278 on inflammatory biomarkers (C-reactive protein [CRP] and faecal calprotectin); and to describe the pharmacokinetics and immunogenicity of TILA-278 over the induction period.

Study Design and Methodology

This was a Phase 2b, randomised, double-blind, placebo-controlled, parallel-group induction study. Following a screening period of up to 5 weeks, eligible subjects were randomised 1:1:1 to receive TILA-278 High dose, TILA-278 Low dose, or matching placebo administered subcutaneously. Randomisation was stratified by baseline modified Mayo severity (4–6 vs 7–9) and by prior biologic exposure (biologic-naïve vs biologic-experienced).

Subjects, investigators, site staff, and the Sponsor study team remained blinded to treatment assignment throughout the double-blind induction period. Blinding was maintained through the use of identical prefilled syringes, an interactive response technology (IRT) system, and a matched number of subcutaneous injections at each dosing visit regardless of treatment assignment. The double-blind induction period was 12 weeks in duration, with scheduled study visits at Weeks 0 (baseline), 2, 4, 8, and 12. Study drug was administered at Weeks 0, 2, 4, and 8, and the primary efficacy assessment was performed at Week 12. Endoscopies at baseline and Week 12 were read by a central reader blinded to treatment assignment, visit sequence, and subject identity.

The scientific rationale reflects the dual mechanism of TILA-278: antagonism of TL1A dampens TH1/TH17-driven mucosal inflammation and intestinal fibrosis, while agonism at the IL-22 receptor promotes epithelial regeneration and mucosal-barrier repair. These complementary anti-inflammatory and mucosal-healing activities were hypothesised to produce induction of remission superior to placebo.

Number of Subjects (Planned and Analysed)

Planned: approximately 900 subjects (approximately 300 per treatment group).

Screened: 1700. Randomised: 900 (TILA-278 High 299; TILA-278 Low 300; Placebo 301).

Analysed — Full Analysis Set (FAS): the FAS comprised all randomised subjects who received at least one dose of study drug and had at least one post-baseline efficacy assessment, totalling 840 subjects: TILA-278 High 284; TILA-278 Low 283; Placebo 273.

Analysed — Safety Analysis Set: all randomised subjects who received at least one dose of study drug: TILA-278 High 284; TILA-278 Low 283; Placebo 273.

Diagnosis and Main Criteria for Inclusion

Adults aged 18 to 75 years with an established diagnosis of ulcerative colitis and moderately to severely active disease at baseline, defined by a baseline modified Mayo score of 4 to 9 (inclusive) with a centrally read endoscopic subscore ≥ 2. Eligible subjects had an inadequate response to, loss of response to, or intolerance of conventional therapy and/or approved biologic or targeted therapy. Key exclusion criteria included Crohn's disease or indeterminate colitis, disease limited to the rectum, current or planned surgery for UC, clinically significant active infection, and other conditions that in the judgment of the investigator would confound assessment or compromise subject safety.

Test Product, Reference Therapy, and Duration of Treatment

TILA-278 150 mg/mL solution for injection was supplied as identical single-use prefilled syringes each delivering 2 mL (300 mg):

• TILA-278 High dose: 600 mg administered subcutaneously at Weeks 0, 2, 4, and 8 as two injections (2 × 300 mg TILA-278).
• TILA-278 Low dose: 300 mg administered subcutaneously at Weeks 0, 2, 4, and 8 as one TILA-278 injection (300 mg) and one matching placebo injection.
• Reference therapy: matching placebo (identical 2 mL prefilled syringe, no active ingredient) administered subcutaneously on the same schedule (two injections at Weeks 0, 2, 4, and 8).

To preserve the blind, all subjects received two subcutaneous injections of identical appearance at each dosing visit. Study drug batches: TL278-DP-2308 and TL278-DP-2402; placebo batch: PLA-278-2307. Batch-to-subject allocation is provided in Appendix 16.1.6. The treatment duration was a 12-week double-blind induction period, with the primary efficacy endpoint assessed at Week 12.

Criteria for Evaluation

Efficacy. The primary efficacy endpoint was clinical remission at Week 12, defined as a modified Mayo score ≤ 2 with no individual subscore > 1. Key secondary efficacy endpoints were the change from baseline in the modified Mayo score at Week 12 and endoscopic improvement at Week 12 (centrally read endoscopic subscore ≤ 1). Additional endpoints included changes from baseline in CRP and faecal calprotectin.

Safety. Safety was evaluated on the basis of treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, adverse events leading to study discontinuation, injection-site reactions, clinical laboratory parameters, vital signs, and immunogenicity (anti-drug antibodies). Adverse events were coded using MedDRA and graded for severity and relationship to study drug by the investigator.

Pharmacokinetics and Immunogenicity

Consistent with a monoclonal antibody directed at soluble and cell-surface targets, TILA-278 exhibits target-mediated drug disposition (TMDD): non-linear, target-driven clearance predominates at low concentrations and transitions to slower, IgG1-typical linear elimination once target binding is saturated. Subcutaneous administration produces sustained systemic exposure, and FcRn-mediated recycling contributes to the extended terminal half-life; the observed pharmacokinetics support the every-other-week induction regimen. Immunogenicity was assessed using a validated tiered assay (screening, confirmatory, and titre determination) with a cell-based neutralising-antibody assay. Treatment-emergent anti-drug antibodies over the 12-week induction period were low in incidence and had no discernible effect on exposure, efficacy, or safety. Detailed pharmacokinetic and immunogenicity results are presented in Sections 11.4.3 and 12 of the full report.

Statistical Methods

The planned sample size of approximately 900 randomised subjects (approximately 300 per group) provided greater than 90% power to detect the anticipated between-group difference in the Week 12 clinical remission rate at a two-sided significance level of 0.05, allowing for the stratified design and expected non-response rates.

The primary analysis population for efficacy was the FAS. The primary endpoint (clinical remission at Week 12) was analysed as a binary outcome; the difference in remission proportions between each TILA-278 group and placebo was estimated with the associated 95% confidence interval (CI) and tested using a Cochran-Mantel-Haenszel approach stratified by the randomisation strata (baseline modified Mayo severity and prior biologic exposure). Subjects with missing Week 12 status were classified as non-responders (non-responder imputation).

Change from baseline in the modified Mayo score at Week 12 was analysed using an analysis of covariance (ANCOVA) model with treatment group as a factor and baseline modified Mayo score as a covariate; least-squares (LS) mean changes, between-group differences versus placebo, 95% CIs, and p-values were derived from the model. Endoscopic improvement was analysed analogously to the primary endpoint.

Control of the overall type I error rate at a two-sided alpha of 0.05 was maintained by a pre-specified fixed-sequence hierarchical testing procedure: (1) clinical remission, High versus placebo; (2) clinical remission, Low versus placebo; (3) change in modified Mayo, High versus placebo; (4) change in modified Mayo, Low versus placebo; (5) endoscopic improvement, High versus placebo; (6) endoscopic improvement, Low versus placebo. Each hypothesis was tested only if the preceding hypothesis in the sequence achieved statistical significance. Pre-specified sensitivity analyses (including tipping-point and multiple-imputation approaches for missing data) supported the primary analysis. Safety data were summarised descriptively on the Safety Analysis Set.

Summary of Results

Subject Disposition

Of 1700 subjects screened, 900 were randomised (299 High, 300 Low, 301 Placebo). The FAS comprised 284, 283, and 273 subjects, respectively. Treatment groups were balanced with respect to baseline demographic and disease characteristics, including baseline modified Mayo severity and prior biologic exposure. Study discontinuation was more frequent in the placebo group (10.6%) than in the TILA-278 High (6.0%) and Low (6.0%) groups, driven mainly by lack of efficacy.

Efficacy

The study met its primary endpoint. Clinical remission at Week 12 was achieved by a significantly greater proportion of subjects in both TILA-278 groups than in the placebo group, with a clear dose-ordered response (High > Low > Placebo). Both key secondary comparisons of change from baseline in the modified Mayo score were also statistically significant in favour of TILA-278, consistent with the hierarchical testing sequence.

Table 1. Clinical Remission at Week 12 — Primary Endpoint (FAS; Non-Responder Imputation)

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

Table 2. Change From Baseline in Modified Mayo Score at Week 12 — Key Secondary Endpoint (FAS; ANCOVA)

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

Table 3. Endoscopic Improvement at Week 12 — Key Secondary Endpoint (FAS; Centrally Read Endoscopic Subscore ≤ 1)

Parameter	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
Endoscopic improvement rate, %	48.9	27.9	6.2

Endoscopic improvement at Week 12 demonstrated a consistent, dose-ordered benefit favouring TILA-278 over placebo, in line with the primary and modified Mayo change results. Reductions in the inflammatory biomarkers CRP and faecal calprotectin were observed in the active treatment arms and were proportionate to the magnitude of modified Mayo improvement, providing objective, mechanism-consistent support for the clinical findings — the biomarker signal being consistent with both TL1A-driven suppression of mucosal inflammation and IL-22 receptor-driven epithelial healing.

Safety

TILA-278 was well tolerated over the 12-week induction period at both dose levels, and no dose-dependent safety signal was identified. The overall incidence of TEAEs was numerically lower in each TILA-278 group than in the placebo group (38.4% [High] and 46.3% [Low] versus 47.6% [Placebo]). Serious adverse events were infrequent in all groups (High 1.1%, Low 0.0%, Placebo 1.5%). Three deaths occurred during the study (2 High, 0 Low, 1 Placebo); all were assessed by the investigator as unrelated to study drug. The higher rate of study discontinuation in the placebo group was driven mainly by lack of efficacy.

Table 4. Overall Summary of Adverse Events (Safety Analysis Set), n (%)

Category	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
≥1 treatment-emergent AE	109 (38.4)	131 (46.3)	130 (47.6)
Serious AE	3 (1.1)	0 (0.0)	4 (1.5)
Deaths	2 (0.7)	0 (0.0)	1 (0.4)
Discontinued study	17 (6.0)	17 (6.0)	29 (10.6)

Table 5. Most Frequent Treatment-Emergent Adverse Events by Preferred Term (Safety Analysis Set), n (%)

Preferred term	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)

Worsening of ulcerative colitis was reported more frequently in the placebo group, consistent with the observed efficacy of TILA-278. Injection-site reactions were more frequent with active subcutaneous drug than with placebo and represented the principal drug-attributable finding; these events were predominantly mild to moderate and transient and rarely led to treatment discontinuation. No dose-dependent safety signal was identified, and the overall adverse-event profile was consistent with the anti-TL1A/IL-22 receptor mechanism of action and with the monoclonal-antibody class. Anti-drug antibody findings were low in incidence and without apparent clinical consequence. Pharmacokinetic and immunogenicity results are presented in Sections 11.4.3 and 12 of the report.

Conclusion and Basis for Dose Selection

In this Phase 2b, randomised, double-blind, placebo-controlled induction study in adults with moderately to severely active ulcerative colitis, TILA-278 met its primary endpoint. Both dose levels produced statistically significant and clinically meaningful increases in the Week 12 clinical remission rate relative to placebo (High 37.3% and Low 16.2% vs Placebo 0.7%), with a clear dose-ordered response and a very low placebo remission rate. Both key secondary comparisons of change from baseline in the modified Mayo score were statistically significant in favour of TILA-278 (LS-mean difference vs placebo: High −2.36; Low −1.77; both p < 0.0001), and endoscopic improvement (48.9% High and 27.9% Low vs 6.2% Placebo) and biomarker reductions were directionally consistent.

TILA-278 was well tolerated at both doses over the 12-week induction period, with no dose-dependent safety signal; injection-site reactions were the principal drug-attributable finding, and the three reported deaths were all assessed as unrelated to study drug. The magnitude and consistency of the response across clinical, endoscopic, and biomarker endpoints support the dual mechanism of action and a favourable benefit-risk profile. On the basis of the dose-ordered efficacy and the comparable tolerability of the two dose levels, the High dose (600 mg subcutaneously every other week during induction) was selected for advancement into the pivotal Phase 3 induction and maintenance programme, together with the primary and key secondary endpoints validated in this study.

Regulatory and Quality Framework

The clinical study report is prepared in accordance with ICH E3, and the study was conducted in accordance with ICH E6(R2) Good Clinical Practice. The intended marketing application is a Biologics License Application under 21 CFR Part 601. The drug substance is a CHO cell culture-derived bispecific monoclonal antibody purified by Protein A affinity capture followed by polishing chromatography and orthogonal viral-clearance steps; quality attributes are controlled to ICH Q6B specifications, viral safety is assured in accordance with ICH Q5A(R2), and stability is established in accordance with ICH Q5C. The nonclinical programme was conducted in accordance with ICH S6(R1). The finished product is presented as a 150 mg/mL solution in a single-use prefilled syringe for subcutaneous administration.

Date of the Report

30 June 2026.