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Protocol Synopsis

Field	Value
Document ID	PROT-201
Version	1.0
Compound	TILA-278 (anti-TL1A antagonist / IL-22R agonist bispecific)
Standard	ICH E6(R3)
Confidentiality	Confidential

Protocol synopsis for Study TILA278-201, the Phase 2b induction study of TILA-278 in moderate-to-severe ulcerative colitis.

Change History

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

Clinical Study Report Synopsis

This synopsis summarizes the design and principal results of Study TILA278-201, a completed Phase 2b induction study of TILA-278 in adults with moderate-to-severe ulcerative colitis. Detailed methods, definitions, analytic conventions, and complete results are provided in the corresponding sections of the full clinical study report.

Administrative Information

Item	Detail
Study title	A Phase 2b, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of TILA-278 as Induction Therapy in Adults with Moderate-to-Severe Ulcerative Colitis
Sponsor	Virtual Biopharma Inc.
Protocol number	TILA278-201
Investigational product	TILA-278, an anti-TL1A (TNFSF15) antagonist / IL-22R agonist bispecific monoclonal antibody, administered subcutaneously
Development phase	Phase 2b
Indication	Moderate-to-severe active ulcerative colitis (induction of remission)
Study design	Randomized, double-blind, placebo-controlled, parallel-group, three-arm induction study
Planned enrollment	Approximately 1700 subjects screened to randomize 900 subjects (1:1:1)
Subjects randomized / analyzed	900 randomized; 840 in the Full Analysis Set (TILA-278 High 284, TILA-278 Low 283, Placebo 273)
Treatment duration	12-week induction period
Number of treatment arms	3 (TILA-278 High, TILA-278 Low, Placebo)

Background and Rationale

Ulcerative colitis (UC) is a chronic, relapsing inflammatory disease of the colonic mucosa. Despite the availability of advanced therapies, a substantial proportion of patients with moderate-to-severe disease fail to achieve or maintain corticosteroid-free remission and mucosal healing, underscoring the need for mechanisms that combine potent anti-inflammatory activity with active restoration of the epithelial barrier.

TILA-278 is a bispecific antibody engineered to simultaneously antagonize TL1A (TNFSF15) and agonize IL-22 signaling. TL1A antagonism dampens TH1/TH17-driven mucosal inflammation and attenuates intestinal fibrosis, while IL-22R agonism drives epithelial regeneration and mucosal-barrier repair. These complementary anti-inflammatory and mucosal-healing activities provided the mechanistic rationale for evaluating TILA-278 as induction therapy in moderate-to-severe UC. This study was designed to establish the efficacy and safety of two subcutaneous dose regimens of TILA-278 relative to placebo over a 12-week induction period and to characterize the dose-response relationship to inform subsequent Phase 3 dose selection.

Objectives and Corresponding Endpoints

Type	Objective	Endpoint
Primary	To evaluate the efficacy of TILA-278 versus placebo in inducing clinical remission at Week 12	Clinical remission at Week 12, defined as a modified Mayo score ≤ 2 with no individual subscore > 1
Key secondary	To evaluate the effect of TILA-278 versus placebo on overall disease activity at Week 12	Change from baseline in modified Mayo score at Week 12
Key secondary	To evaluate the effect of TILA-278 versus placebo on endoscopic disease activity at Week 12	Endoscopic improvement at Week 12, defined as a centrally read endoscopy subscore ≤ 1
Secondary	To evaluate additional measures of clinical benefit	Clinical response at Week 12 (reduction in modified Mayo score ≥ 2 points and ≥ 30% from baseline, with a decrease in rectal bleeding subscore ≥ 1 or an absolute rectal bleeding subscore ≤ 1); symptomatic remission at Week 12 (rectal bleeding subscore of 0 and stool frequency subscore ≤ 1 with no increase from baseline)
Secondary	To characterize the safety and tolerability of TILA-278	Incidence of treatment-emergent adverse events, serious adverse events, injection-site reactions, and adverse events leading to discontinuation; clinically significant changes in vital signs and laboratory parameters
Exploratory	To evaluate the effect of TILA-278 on objective markers of inflammation	Change from baseline in C-reactive protein (CRP) and faecal calprotectin over time
Exploratory	To characterize pharmacokinetics and immunogenicity	Serum TILA-278 concentrations; incidence and titre of anti-drug antibodies (ADA)

Study Design

Protocol TILA278-201 was a Phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group study evaluating a 12-week induction course of TILA-278 in adults with moderate-to-severe active UC. Eligible subjects were randomized in a 1:1:1 ratio to receive TILA-278 High, TILA-278 Low, or matching placebo administered subcutaneously.

Randomization was performed centrally via an interactive response technology (IRT) system and was stratified by baseline modified Mayo severity (4–6 vs 7–9) and prior biologic exposure (yes vs no). Subjects, investigators, site personnel, and the sponsor study team remained blinded to treatment assignment throughout the induction period. To preserve the blind, all subjects received an identical number and volume of subcutaneous injections at each dosing visit.

The study comprised three periods:

• Screening period (up to 35 days): assessment of eligibility, including centrally read baseline endoscopy.
• Double-blind induction period (Week 0 to Week 12): study drug administration and protocol assessments at visits at Weeks 0, 2, 4, 8, and 12.
• Post-treatment follow-up / disposition: subjects completing Week 12 were assessed for eligibility to enter a separate maintenance or long-term extension study, or entered safety follow-up.

The Week 12 visit constituted the End-of-Treatment (EOT) visit at which the primary and key secondary endpoints were assessed.

Study Population

The study enrolled adults with an established diagnosis of moderate-to-severe active UC who had demonstrated an inadequate response, loss of response, or intolerance to prior therapy. Key eligibility criteria are summarized below; the full criteria are specified in the protocol.

Key Inclusion Criteria

1. Male or female, 18 to 75 years of age (inclusive) at screening.
2. Documented diagnosis of ulcerative colitis established at least 3 months prior to screening, confirmed by endoscopic and histologic evidence.
3. Moderate-to-severe active UC, defined as a baseline modified Mayo score of 4 to 9, with a centrally read endoscopy subscore ≥ 2 and a rectal bleeding subscore ≥ 1.
4. Minimum disease extent of ≥ 15 cm from the anal verge.
5. Demonstrated inadequate response, loss of response, or intolerance to at least one prior therapy for UC, including corticosteroids, immunomodulators (thiopurines), biologic agents (anti-TNF, anti-integrin, or anti-IL-12/23), or Janus kinase inhibitors.
6. If receiving concomitant UC therapy, on stable permitted doses per protocol prior to randomization.
7. Willing and able to provide written informed consent and to comply with the visit and assessment schedule.

Key Exclusion Criteria

1. Diagnosis of Crohn's disease, indeterminate colitis, microscopic colitis, or isolated ulcerative proctitis (disease limited to < 15 cm from the anal verge).
2. Current evidence of fulminant colitis, toxic megacolon, or clinical signs suggestive of impending bowel perforation.
3. Prior total or subtotal colectomy, or anticipated need for UC-related surgery during the study.
4. Active or clinically significant chronic infection; latent or active tuberculosis; known infection with HIV, hepatitis B, or hepatitis C.
5. Positive stool assessment for enteric pathogens, including Clostridioides difficile toxin, at screening.
6. History of malignancy within 5 years, excluding adequately treated non-melanoma skin cancer or in situ cervical carcinoma.
7. Prior exposure to any agent targeting TL1A or IL-22.
8. Clinically significant hepatic, renal, cardiovascular, neurologic, or hematologic condition that, in the investigator's judgment, would compromise subject safety or interpretation of study results.
9. Pregnant or breastfeeding women, or women of childbearing potential unwilling to use highly effective contraception.

Determination of Sample Size

Approximately 900 subjects were planned for randomization in a 1:1:1 ratio (approximately 300 subjects per arm). To achieve the target randomization, approximately 1700 subjects were expected to be screened.

The sample size was driven by the primary endpoint of clinical remission at Week 12. Assuming a clinical remission rate of approximately 8% in the placebo arm, 300 subjects per arm provided at least 90% power to detect a between-group difference of ≥ 14 percentage points versus placebo for each active dose, using a chi-square test at a two-sided significance level of 0.05, with strong control of the family-wise type I error rate across the two dose-versus-placebo comparisons and the key secondary endpoints ensured by the pre-specified fixed-sequence testing hierarchy (see Statistical Methods). This sample size also provided greater than 90% power for the key secondary endpoint of change from baseline in modified Mayo score, assuming a between-group difference of approximately 0.9 points and a common standard deviation of 2.5 points, analyzed by analysis of covariance (ANCOVA) at a two-sided significance level of 0.05.

The per-arm randomization target of 300 incorporated an allowance of approximately 5–7% for subjects who were randomized but not evaluable for the Full Analysis Set (e.g., subjects who did not receive study drug or lacked a post-baseline efficacy assessment).

Parameter	Value
Randomization ratio (High: Low: Placebo)	1: 1: 1
Planned randomized subjects per arm	~300
Total planned randomized	~900
Planned screened	~1700
Primary endpoint	Clinical remission at Week 12
Assumed placebo remission rate	~8%
Target power (per active dose vs placebo)	≥ 90%
Two-sided significance level (family-wise)	0.05
Multiplicity control	Pre-specified fixed-sequence (hierarchical) testing procedure

Study Treatments

Study drug and matching placebo were supplied as sterile solutions for subcutaneous injection. Study drug was administered at the clinic at Weeks 0, 2, 4, and 8; the Week 12 visit was an assessment visit with no dosing. All subjects received matched injection volumes at each dosing visit to maintain the double-blind.

Treatment arm	Week 0 (loading)	Weeks 2, 4, and 8	Route	Total doses
TILA-278 High	600 mg SC	300 mg SC	Subcutaneous	4
TILA-278 Low	300 mg SC	150 mg SC	Subcutaneous	4
Placebo	Volume-matched placebo SC	Volume-matched placebo SC	Subcutaneous	4

Permitted background UC medications (aminosalicylates, stable-dose oral corticosteroids with a protocol-defined taper, and thiopurines) were maintained at stable doses through the induction period unless a change was medically required. Initiation of new advanced therapies, prohibited immunomodulators, and UC-related surgery were not permitted during the induction period; subjects requiring such interventions were managed per protocol and handled as treatment failures in the efficacy analyses.

Statistical Methods

Analysis populations

• Full Analysis Set (FAS): all randomized subjects who received at least one dose of study drug and had a baseline and at least one post-baseline efficacy assessment, analyzed according to randomized treatment. The FAS was the primary population for efficacy analyses.
• Safety Set: all randomized subjects who received at least one dose of study drug, analyzed according to treatment actually received. In this study all treated subjects had a post-baseline assessment, so the Safety Set and the FAS comprised the same subjects (High 284, Low 283, Placebo 273).
• Per-Protocol Set: the subset of the FAS without major protocol deviations affecting the primary endpoint; used for supportive analyses.

Primary endpoint analysis

The primary endpoint (clinical remission at Week 12) was analyzed using a Cochran-Mantel-Haenszel (CMH) test stratified by the randomization stratification factors (baseline modified Mayo severity [4–6 vs 7–9] and prior biologic exposure [yes vs no]), comparing each TILA-278 dose with placebo. The treatment difference in remission rates (risk difference) and its 95% confidence interval were reported. A logistic regression model including terms for treatment, baseline modified Mayo score, and the stratification factors was fitted as a supportive analysis to estimate adjusted odds ratios.

Key secondary endpoint analyses

• Change from baseline in modified Mayo score at Week 12 was analyzed by ANCOVA, with treatment as a fixed factor and baseline modified Mayo score as a covariate. Least-squares (LS) mean changes, LS-mean differences versus placebo, corresponding 95% confidence intervals, and p-values were reported.
• Endoscopic improvement at Week 12 was analyzed using the same stratified CMH approach as the primary endpoint.

Multiplicity control

Strong control of the family-wise type I error rate at a two-sided 0.05 was maintained using a pre-specified hierarchical fixed-sequence testing procedure. Hypotheses were tested in a fixed order beginning with the primary endpoint for the TILA-278 High dose versus placebo, followed by the TILA-278 Low dose versus placebo, and then the key secondary endpoints (change from baseline in modified Mayo score, then endoscopic improvement) for each dose in the same dose order. Each hypothesis was tested at the full two-sided 0.05 level, and testing proceeded to the next hypothesis in the sequence only if the preceding hypothesis was statistically significant; once a hypothesis failed to reach significance, formal confirmatory testing stopped and subsequent comparisons were considered exploratory.

Handling of missing data

• For binary endpoints (clinical remission, endoscopic improvement, clinical response), the primary analysis applied non-responder imputation (NRI): subjects with missing Week 12 status, and subjects who discontinued study treatment due to lack of efficacy, initiated prohibited medication, or underwent UC-related surgery, were classified as non-responders. Sensitivity analyses included tipping-point and multiple-imputation approaches.
• For the continuous endpoint (change from baseline in modified Mayo score), the primary ANCOVA was supported by sensitivity analyses using a mixed-model repeated-measures (MMRM) approach and multiple imputation to assess robustness to the missing-data assumptions.

Continuous variables were summarized using descriptive statistics (n, mean, standard deviation, median, minimum, maximum); categorical variables were summarized using frequencies and percentages. Safety data were summarized descriptively by treatment arm using the Safety Set, with adverse events coded using MedDRA and summarized by system organ class and preferred term.

Subject Disposition and Analysis Populations

Of approximately 1700 subjects screened, 900 were randomized 1:1:1 to TILA-278 High, TILA-278 Low, or placebo. A total of 840 subjects received at least one dose of study drug and were included in the Full Analysis Set and Safety Set; 60 randomized subjects (High 15, Low 17, Placebo 28) were not dosed or lacked a post-baseline efficacy assessment and were excluded from the analysis populations. Study discontinuation was more frequent in the placebo arm and was driven mainly by lack of efficacy.

Disposition / population	TILA-278 High	TILA-278 Low	Placebo	Total
Randomized	299	300	301	900
Full Analysis Set / Safety Set	284	283	273	840
Discontinued study	17 (6.0%)	17 (6.0%)	29 (10.6%)	63
Deaths	2 (0.7%)	0	1 (0.4%)	3

Percentages for discontinuation and deaths are based on the Full Analysis Set / Safety Set (High 284, Low 283, Placebo 273).

Efficacy Results

Primary endpoint — Clinical remission at Week 12 (FAS; NRI). TILA-278 produced a statistically significant, clinically meaningful, and clearly dose-ordered effect on the primary endpoint. Clinical remission (modified Mayo score ≤ 2 with no individual subscore > 1) was achieved by 106 of 284 subjects (37.3%) in the TILA-278 High arm and 46 of 283 subjects (16.2%) in the TILA-278 Low arm, compared with 2 of 273 subjects (0.7%) receiving placebo. The stratified 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. The dose ordering (High > Low > placebo) was consistent with a dose-response relationship.

Analysis (Week 12)	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
Clinical remission, n (%)	106 (37.3%)	46 (16.2%)	2 (0.7%)
Risk difference vs placebo (95% CI)	+36.6 (30.9 to 42.3)	+15.5 (11.1 to 19.9)	—
p-value vs placebo	< 0.0001	< 0.0001	—

Key secondary endpoint — Change from baseline in modified Mayo score at Week 12 (FAS; ANCOVA). The first key secondary endpoint was consistent with the primary result. LS-mean reductions in modified Mayo score were −3.36 in the TILA-278 High arm and −2.76 in the TILA-278 Low arm, versus −1.00 with 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.

Analysis (Week 12)	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
LS-mean change from baseline in modified Mayo	−3.36	−2.76	−1.00
LS-mean difference vs placebo (95% CI)	−2.36 (−2.49 to −2.23)	−1.77 (−1.90 to −1.64)	—
p-value vs placebo	< 0.0001	< 0.0001	—

Endoscopic and biomarker findings. Endoscopic improvement at Week 12, the second key secondary endpoint in the testing hierarchy, was consistent with the reductions in clinical disease activity observed in the active arms. Reductions from baseline in C-reactive protein and faecal calprotectin in the TILA-278 arms tracked the magnitude of modified Mayo improvement, corroborating the clinical findings and supporting mucosal healing. Improvements were most pronounced in the High-dose arm.

Safety Results

TILA-278 was well tolerated over the 12-week induction period, with no dose-dependent safety signal. The proportion of subjects with at least one treatment-emergent adverse event (TEAE) was similar across the arms. Serious adverse events were infrequent, and study discontinuation was more frequent with placebo, driven mainly by lack of efficacy. Three deaths occurred (TILA-278 High 2, placebo 1); all were assessed by the investigator as unrelated to study drug.

Safety parameter, n (%)	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
≥ 1 treatment-emergent adverse event	109 (38.4%)	131 (46.3%)	130 (47.6%)
≥ 1 serious adverse event	3 (1.1%)	0	4 (1.5%)
Deaths	2 (0.7%)	0	1 (0.4%)
Discontinued study	17 (6.0%)	17 (6.0%)	29 (10.6%)

Injection-site reactions were more common with active subcutaneous TILA-278 than with placebo and represented the principal drug-attributable finding. Worsening of ulcerative colitis was reported more frequently with placebo than with active treatment, consistent with the efficacy findings. The most frequently reported adverse events are shown below.

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%)

The overall adverse-event profile was consistent with the anti-TL1A/IL-22 mechanism and the therapeutic antibody class. There was no evidence of a dose-dependent safety signal; injection-site reactions were the principal drug-attributable finding, and inflammatory markers (CRP and faecal calprotectin) declined in the active arms in proportion to the improvement in modified Mayo score.

Data Safety Monitoring Board

An independent Data Safety Monitoring Board (DSMB) provided ongoing oversight of subject safety throughout the study. The DSMB operated under a pre-specified charter that defined its composition (independent gastroenterologists/clinical experts and an independent statistician), meeting frequency, review scope, and decision-making procedures. The DSMB reviewed unblinded safety data — including deaths, serious adverse events, adverse events leading to discontinuation, injection-site reactions, and laboratory safety parameters — at pre-specified intervals during enrollment and treatment.

Unblinded safety reports were prepared by an independent statistical group that was functionally separate from the blinded sponsor study team, preserving the integrity of the double-blind for the conduct of the study. The DSMB could recommend continuation, modification, temporary suspension, or termination of the study based on its benefit–risk assessment. No formal interim efficacy analysis for early stopping was planned; the DSMB's role was confined to safety oversight.

Schedule of Assessments

Protocol assessments were performed at screening and at scheduled induction-period visits at Weeks 0, 2, 4, 8, and 12 (End of Treatment / Early Termination). An "X" indicates the assessment was performed at that visit.

Assessment	Screening (Day −35 to −1)	Week 0 (Day 1)	Week 2	Week 4	Week 8	Week 12 (EOT/ET)
Informed consent	X
Inclusion/exclusion criteria	X	X
Demographics and medical/UC history	X
Randomization (IRT)		X
Study drug administration (SC)		X	X	X	X
Full modified Mayo score (incl. endoscopy)	X					X
Partial Mayo (stool frequency, rectal bleeding)		X	X	X	X	X
Centrally read endoscopy	X					X
Physical examination	X	X				X
Vital signs	X	X	X	X	X	X
Body weight	X					X
Hematology and serum chemistry	X	X	X	X	X	X
C-reactive protein (CRP)	X	X	X	X	X	X
Faecal calprotectin	X	X		X	X	X
Stool assessment for enteric pathogens (incl. C. difficile)	X
Pregnancy test (WOCBP)	X	X		X	X	X
Pharmacokinetic sampling		X	X	X	X	X
Anti-drug antibody (immunogenicity) sampling		X		X		X
Injection-site reaction assessment		X	X	X	X
Adverse event monitoring	X (from consent)	X	X	X	X	X
Concomitant medication review	X	X	X	X	X	X

Conclusions

In this Phase 2b induction study, both subcutaneous TILA-278 regimens produced statistically significant, clinically meaningful, and dose-ordered improvements in clinical remission and in overall modified Mayo disease activity versus placebo at Week 12, supported by endoscopic and inflammatory-biomarker findings consistent with mucosal healing. TILA-278 was well tolerated, with injection-site reactions the principal drug-attributable finding and no dose-dependent safety signal. The benefit–risk profile observed with the High-dose regimen supports advancement of TILA-278 into Phase 3 evaluation in adults with moderate-to-severe ulcerative colitis.

Abbreviations: ADA, anti-drug antibody; AE, adverse event; ANCOVA, analysis of covariance; CI, confidence interval; CMH, Cochran-Mantel-Haenszel; CRP, C-reactive protein; DSMB, Data Safety Monitoring Board; EOT, End of Treatment; ET, Early Termination; FAS, Full Analysis Set; IL-22, interleukin-22; IRT, interactive response technology; ISR, injection-site reaction; LS, least-squares; MedDRA, Medical Dictionary for Regulatory Activities; MMRM, mixed-model repeated measures; NRI, non-responder imputation; PT, preferred term; SAE, serious adverse event; SC, subcutaneous; SOC, system organ class; TEAE, treatment-emergent adverse event; TL1A, TNF-like ligand 1A (TNFSF15); UC, ulcerative colitis; WOCBP, women of childbearing potential.