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Clinical Study Report (TILA278-201)

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

Clinical Study Report — TILA278-201

Sponsor: Virtual Biopharma Inc.
Investigational product: TILA-278, a humanized IgG1 bispecific monoclonal antibody that simultaneously antagonizes TNF-like ligand 1A (TL1A) and agonizes the interleukin-22 receptor (IL-22R). The molecule is produced by recombinant expression in a Chinese hamster ovary (CHO) host cell line and purified by a Protein A capture step followed by orthogonal polishing chromatography; it is formulated for subcutaneous administration. TL1A antagonism is intended to interrupt TL1A/DR3 co-stimulation of effector T cells and innate lymphoid cells, delivering anti-inflammatory and anti-fibrotic activity, while IL-22R agonism is intended to drive intestinal epithelial regeneration, mucus/antimicrobial peptide production and mucosal barrier restoration. The dual mechanism was designed to combine suppression of the mucosal inflammatory cascade with active promotion of epithelial healing in ulcerative colitis (UC).
Indication studied: Moderate-to-severe active UC.
Development context: The clinical program supports a Biologics License Application submitted under 21 CFR Part 601. The quality, nonclinical and clinical strategy is aligned with ICH Q5A(R2), Q5C, Q6B and S6(R1) for a recombinant monoclonal antibody. Consistent with S6(R1), the cynomolgus monkey was the sole pharmacologically relevant toxicology species, and standard small-molecule assessments (genotoxicity, carcinogenicity, hERG and a thorough QT study) were not warranted for this modality and were not conducted.

9 Investigational Plan

9.1 Overall study design and plan

TILA278-201 was a Phase 2b, randomized, double-blind, placebo-controlled, parallel-group, multicenter induction study in adults with moderate-to-severe active UC (N randomized 900). Eligible subjects were randomized 1:1:1 to one of two subcutaneous dose levels of TILA-278 (TILA-278 High or TILA-278 Low) or to matching placebo, and were treated over a 12-week induction period with the primary assessment at Week 12. Randomization was stratified by prior exposure to advanced/biologic therapy (biologic-exposed vs biologic-naïve) and by baseline disease activity (baseline modified Mayo score). Study drug was administered subcutaneously on a fixed induction schedule (Weeks 0, 2, 4 and 8), with placebo injections matched for volume, presentation and schedule to preserve the double blind. The primary endpoint was clinical remission (modified Mayo) at Week 12.

Subject flow: 1700 subjects were screened and 900 were randomized (299 to TILA-278 High, 300 to TILA-278 Low, 301 to placebo). The Full Analysis Set (FAS) comprised 840 subjects (284 High, 283 Low, 273 placebo), defined as all randomized subjects who received at least one dose of study drug and had a baseline plus at least one post-baseline efficacy assessment. The safety population comprised all randomized subjects who received any study drug (299/300/301). Study drug was discontinued in 17, 17 and 29 subjects in the High, Low and placebo arms, respectively; the higher attrition on placebo was driven predominantly by lack of efficacy and worsening UC.

9.2 Study objectives

• Primary: to evaluate the efficacy of TILA-278 versus placebo in inducing clinical remission (modified Mayo score) at Week 12 in moderate-to-severe UC.
• Key secondary: to evaluate the effect of TILA-278 versus placebo on the change from baseline in the modified Mayo score and on endoscopic improvement at Week 12.
• Additional secondary/exploratory: clinical response, symptomatic (partial Mayo) remission, endoscopic-histologic mucosal improvement, biomarkers of inflammation (fecal calprotectin, high-sensitivity C-reactive protein) and epithelial repair, serum pharmacokinetics, and immunogenicity (anti-drug antibodies, ADA).
• Safety: to characterize the safety and tolerability of the two dose levels versus placebo over the induction period.

9.3 Selection of the study population

Key inclusion criteria were adults with a diagnosis of UC established by endoscopy and histology, moderate-to-severe disease activity by modified Mayo score with a centrally read endoscopic subscore consistent with active disease, and an inadequate response, loss of response or intolerance to conventional and/or advanced UC therapies. Key exclusion criteria included Crohn's disease or indeterminate colitis, prior colectomy or planned surgery, current toxic megacolon or fulminant colitis, clinically significant active infection (including tuberculosis and hepatitis B/C screening abnormalities), and any condition that would confound efficacy or safety assessment. Concomitant stable-dose oral aminosalicylates and tapering corticosteroids were permitted per protocol; other advanced therapies were prohibited during the induction period.

9.4 Treatments administered

TILA-278 was supplied as a sterile liquid for subcutaneous injection. Subjects assigned to active treatment received either the higher (TILA-278 High) or lower (TILA-278 Low) subcutaneous dose level at Weeks 0, 2, 4 and 8; subjects assigned to placebo received matching subcutaneous injections on the same schedule. Study drug was administered at the site by trained personnel to maintain blinding and to standardize exposure across arms.

9.5 Randomization and blinding

Subjects were assigned to treatment via a centralized interactive response technology system using a permuted-block randomization schedule within the stratification factors. The study was double-blind: subjects, investigators, site personnel and the sponsor study team were blinded to treatment assignment. Endoscopies were read by a central reader blinded to treatment, visit and subject identity to minimize assessment bias for the endoscopic components of the modified Mayo score.

9.6 Efficacy and safety variables

The modified Mayo score (composite of stool frequency, rectal bleeding and centrally read endoscopic subscores) was the basis for the efficacy endpoints. Clinical remission at Week 12 was defined a priori as a modified Mayo score ≤ 2 with no individual subscore > 1. Endoscopic improvement was defined as a Mayo endoscopic subscore ≤ 1. Safety variables included treatment-emergent adverse events (TEAEs), serious adverse events (SAEs), deaths, discontinuations due to adverse events, injection-site reactions and hypersensitivity events, infections (including serious and opportunistic infections), laboratory parameters (hematology, chemistry, hepatic panel), vital signs and 12-lead electrocardiograms. Given the target-mediated disposition expected for this antibody, serum TILA-278 concentrations and ADA were collected to support pharmacokinetic (PK) and immunogenicity assessment.

9.7 Statistical methods

The primary efficacy analysis compared each TILA-278 dose level with placebo for the proportion of subjects in clinical remission at Week 12 in the FAS, using a Cochran–Mantel–Haenszel approach stratified by the randomization factors, with non-responder imputation (NRI) applied to subjects with missing Week 12 data or who discontinued. The continuous key secondary endpoint (change from baseline in modified Mayo score) was analyzed by a mixed-effects model for repeated measures (MMRM) including all randomized subjects with observed post-baseline data, with treatment, visit, treatment-by-visit interaction, stratification factors and baseline score as covariates; least-squares (LS) mean differences versus placebo are reported with 95% confidence intervals. Endoscopic improvement was analyzed analogously to the primary endpoint. Type I error was controlled across the primary and key secondary hypotheses using a pre-specified hierarchical (graphical) testing procedure, ordered by dose and endpoint. The planned sample size of 900 randomized subjects provided high power to detect the anticipated dose-ordered treatment effect on clinical remission while allowing for screen-failure and non-evaluable attrition. Reported p-values of 0.0000 correspond to p < 0.0001. Sensitivity analyses (including observed-case, tipping-point and alternative imputation strategies) were pre-specified to assess the robustness of the primary result.

11 Efficacy Evaluation

Efficacy demonstrated a clear, dose-ordered and statistically significant benefit for both TILA-278 dose levels over placebo at the end of the 12-week induction period, consistent with the intended dual mechanism of TL1A antagonism (control of the mucosal inflammatory response) plus IL-22R agonism (promotion of epithelial and mucosal healing).

Key secondary endpoint — LS-mean change from baseline in modified Mayo score (MMRM)

Arm	N	LS-mean Δ Modified Mayo Score @ Wk 12 (points)	Diff vs placebo (95% CI)	p
TILA-278 High	299	-3.36	-2.36 (-2.49, -2.23)	0.0000
TILA-278 Low	300	-2.76	-1.77 (-1.90, -1.64)	0.0000
Placebo	301	-1.00	— (reference)	—

Both dose levels produced a significantly greater reduction in the modified Mayo score than placebo, with LS-mean differences of -2.36 points (High) and -1.77 points (Low), each with a 95% confidence interval excluding zero and p < 0.0001. The magnitude and dose ordering of the continuous treatment effect are consistent with the categorical remission result below.

Responder analysis — Clinical remission (Mayo <= 2)

Arm	N	Responders, n/N	Rate	Risk diff vs placebo (95% CI, %)	p
TILA-278 High	284	106/284	37.3%	36.6% (30.9, 42.3)	0.0000
TILA-278 Low	283	46/283	16.2%	15.5% (11.1, 19.9)	0.0000
Placebo	273	2/273	0.7%	— (reference)	—

The primary endpoint was met for both dose levels. Clinical remission (modified Mayo ≤ 2 with no subscore > 1) at Week 12 was achieved by 37.3% (106/284) of subjects on TILA-278 High and 16.2% (46/283) on TILA-278 Low, versus 0.7% (2/273) on placebo, corresponding to placebo-adjusted differences of 36.6% and 15.5%, respectively (both p < 0.0001). The very low placebo remission rate is consistent with the stringent, centrally read endoscopic component of the composite definition and the treatment-refractory character of the enrolled population. The consistency between the categorical remission result and the continuous MMRM analysis supports the robustness of the primary finding, and pre-specified sensitivity analyses were confirmatory.

Endoscopic improvement at Week 12 (Mayo endoscopic subscore ≤ 1)

Arm	Endoscopic improvement rate @ Wk 12
TILA-278 High	48.9%
TILA-278 Low	27.9%
Placebo	6.2%

Endoscopic improvement, a mucosal-level measure of disease modification, followed the same dose-ordered pattern, achieved by 48.9% (High) and 27.9% (Low) of subjects versus 6.2% on placebo. The separation on this objective, centrally read endpoint is mechanistically aligned with IL-22R–driven epithelial regeneration and barrier restoration acting together with TL1A blockade of the inflammatory drive.

Efficacy was directionally consistent across the pre-specified subgroups, including biologic-naïve and biologic-exposed subjects and baseline disease-severity strata, supporting generalizability of the induction effect across the moderate-to-severe UC population studied.

Pharmacokinetics and immunogenicity

Serum TILA-278 exposure following subcutaneous dosing was consistent with target-mediated drug disposition (TMDD), with nonlinearity at lower concentrations reflecting saturable target-mediated clearance and more dose-proportional behavior at the exposures achieved on the induction regimen; observed exposures were higher for TILA-278 High than TILA-278 Low, in line with the dose-ordered efficacy. Treatment-emergent ADA were monitored throughout. ADA incidence was low, responses were predominantly low-titer and transient, neutralizing antibodies were infrequent, and no clinically meaningful impact of ADA on exposure, efficacy or the safety profile was identified over the induction period.

12 Safety Evaluation

TILA-278 was generally well tolerated at both dose levels over the 12-week induction period, with an overall adverse-event burden comparable to placebo and no new safety signal attributable to the dual mechanism. Safety is summarized for the safety population (all randomized subjects who received study drug).

Arm	N	≥1 TEAE	SAE	Deaths	Discontinued
TILA-278 High	299	109	3	2	17
TILA-278 Low	300	131	0	0	17
Placebo	301	130	4	1	29

The proportion of subjects with at least one TEAE was similar across the active arms and placebo (109, 131 and 130 subjects, respectively). SAEs were infrequent and were most numerous in the placebo arm (4), with 3 in TILA-278 High and 0 in TILA-278 Low. Discontinuation of study drug was more frequent on placebo (29) than on either active arm (17 each), consistent with the higher rate of disease worsening in the placebo group.

Most frequent adverse events (subjects, by arm)

Preferred term	TILA-278 High	TILA-278 Low	Placebo
Nasopharyngitis	22	35	20
Headache	21	23	27
Worsening of ulcerative colitis	13	19	35
Anaemia	21	17	28
Arthralgia	10	19	20
Upper respiratory tract infection	11	20	17

The most frequently reported events were nasopharyngitis, headache, worsening of UC, anaemia, arthralgia and upper respiratory tract infection. Worsening of UC and anaemia — both manifestations of underlying active disease — were most frequent on placebo (35 and 28 subjects, respectively), consistent with the efficacy results. The infection-related terms (nasopharyngitis, upper respiratory tract infection) were predominantly mild-to-moderate and non-serious, with no imbalance in serious or opportunistic infections attributable to TILA-278; this is a relevant surveillance area given TL1A-mediated modulation of mucosal immunity.

Deaths, serious adverse events and adverse events of special interest. Deaths were rare (2 in TILA-278 High, 0 in TILA-278 Low, 1 in placebo) and were assessed by the investigators as not related to study drug. SAEs did not cluster by preferred term and showed no pattern suggestive of a treatment-related organ toxicity. Adverse events of special interest for a subcutaneously administered monoclonal antibody — injection-site reactions and hypersensitivity events — were infrequent, generally mild and transient, and did not lead to a meaningful excess of discontinuations on active treatment. Given the IL-22R agonist arm of the molecule, epithelial-proliferation-related events were specifically reviewed; no such signal was observed over the induction period.

Laboratory parameters, vital signs and electrocardiograms. Hematology (including the anaemia observed as a disease manifestation), chemistry and hepatic panels showed no clinically meaningful treatment-related trends, and no pattern consistent with drug-induced liver injury was identified. Vital signs were unremarkable. Twelve-lead electrocardiograms showed no clinically relevant changes; a dedicated thorough QT study was not warranted for a monoclonal antibody and was not conducted, consistent with the modality.

13 Discussion and Overall Conclusions

In this Phase 2b induction study, both dose levels of TILA-278 produced a dose-ordered, statistically significant and clinically meaningful effect at Week 12 across the primary endpoint (clinical remission by modified Mayo), the key secondary continuous endpoint (LS-mean change in modified Mayo score), and the objective, centrally read endoscopic improvement endpoint. The convergence of a symptom-and-endoscopy composite remission result with an objective mucosal-healing endpoint supports genuine disease modification rather than symptomatic effect alone, and is mechanistically coherent with combined TL1A antagonism (dampening the mucosal inflammatory and pro-fibrotic drive) and IL-22R agonism (promoting epithelial regeneration and barrier repair). The safety profile over the induction period was consistent with the class and with a subcutaneously administered IgG1 monoclonal antibody: overall adverse-event rates comparable to placebo, infrequent serious events, and no new signal attributable to the dual mechanism; disease-related events (worsening of UC, anaemia) were most frequent on placebo. Pharmacokinetics were consistent with target-mediated disposition, and immunogenicity was low with no discernible impact on exposure, efficacy or safety. Interpretation is appropriately bounded by the study's 12-week induction design and Phase 2b scope; the higher TILA-278 dose provided the greatest benefit and the overall benefit–risk assessment supports advancement to confirmatory (Phase 3) evaluation of induction and maintenance. Appendices (16.1 study information, 16.2 patient data listings, 16.3 patient narratives, 16.4 individual data) accompany this report. ICH E3.