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Integrated Summary of Efficacy (TILA-278)

Document ID: ISE-201
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH M4E(R2)

Integrated Summary of Efficacy — TILA-278

Product and mechanistic rationale. TILA-278 is a humanized IgG1 bispecific monoclonal antibody produced by recombinant expression in Chinese hamster ovary (CHO) cell culture and administered subcutaneously. The molecule addresses two non-redundant nodes of mucosal immunopathology in Ulcerative Colitis (UC) through a single therapeutic. One arm delivers high-affinity antagonism of TL1A (TNF superfamily member 15, TNFSF15), attenuating TL1A–DR3 signalling that amplifies effector T-cell (Th1/Th17) activation and sustains a pro-inflammatory and pro-fibrotic mucosal environment. The second arm provides agonism at the IL-22 receptor (IL-22R), reproducing the epithelial-restorative programme of IL-22 to drive intestinal epithelial regeneration, mucus and antimicrobial-peptide production, and barrier repair. The design intent is a complementary "dampen inflammation while accelerating mucosal healing" pharmacology that is mechanistically distinct from, and potentially additive to, single-pathway biologics. Because the two epitopes are spatially and functionally independent, the bispecific format is expected to co-localise both activities within the inflamed mucosa.

Regulatory and quality framework. TILA-278 is being developed for licensure as a therapeutic protein under a Biologics License Application (21 CFR Part 601). Manufacturing and control follow the quality expectations applicable to a recombinant monoclonal antibody: ICH Q5A(R2) (viral safety of CHO-derived products), Q5C (stability of biotechnological products), and Q6B (specifications and analytical characterisation, including the bispecific-specific attributes of correct chain pairing and control of aggregates and charge/glycosylation variants), within the nonclinical framework of ICH S6(R1) for biotechnology-derived pharmaceuticals. The downstream process is anchored by Protein A affinity capture followed by orthogonal polishing steps. Consistent with S6(R1) and the target biology, the cynomolgus monkey was the sole pharmacologically relevant toxicology species, as both the TL1A and IL-22R epitopes are engaged and the relevant pathways are conserved in that species. Assessments not scientifically warranted for a large-molecule antibody — standard genotoxicity and carcinogenicity batteries, hERG channel testing, and a dedicated thorough-QT study — were not conducted, consistent with S6(R1)/S7 principles. These attributes bear on efficacy interpretation chiefly through two mechanisms: target-mediated drug disposition (TMDD) shapes exposure, and anti-drug antibody (ADA) formation may modulate response. Both are addressed below.

Disease context and endpoints. Moderate-to-severe UC frequently relapses, and a substantial proportion of patients never respond to, or lose response to, existing advanced therapies, defining a clear therapeutic need. Efficacy in this integrated summary is assessed using the contemporary regulatory standard for UC induction: symptomatic and objective (endoscopic) components combined in the modified Mayo score, with clinical remission as the outcome of principal clinical interest.

Evidence base and study design. The integrated efficacy database for induction of remission in moderate-to-severe UC comprises Study TILA278-201, a Phase 2b randomized, double-blind, placebo-controlled, parallel-group dose-ranging trial (Sponsor: Virtual Biopharma Inc.). Eligible adults with moderate-to-severe active UC were randomized 1:1:1 to a higher-dose TILA-278 regimen (High), a lower-dose TILA-278 regimen (Low), or matching placebo, each administered subcutaneously across a 12-week induction period. Randomization was stratified to balance baseline disease severity and prior advanced-therapy exposure, and blinding was maintained through identical presentation of active and placebo injections. The prespecified primary efficacy endpoint was clinical remission by modified Mayo score at Week 12; the endoscopy contributing to the score was read centrally to reduce assessor variability. As the pivotal induction dataset, TILA278-201 provides the integrated basis for efficacy; no cross-trial pooling was required at this stage, so the "integrated" analysis reflects the full analysis of this single controlled study.

Analysis populations and disposition. Of 1700 patients screened, 900 met eligibility and were randomized: 299 to TILA-278 High, 300 to TILA-278 Low, and 301 to placebo. The Full Analysis Set (FAS), comprising randomized patients who received study drug and had the relevant post-baseline assessment under the intention-to-treat principle, included 840 patients (284 High, 283 Low, 273 placebo); the modest attrition between randomization (900) and FAS (840) reflects patients without the required post-baseline endoscopic assessment or who did not receive study drug. Approximately half of screened patients were randomized, consistent with the objective, centrally-read entry criteria for moderate-to-severe disease. Baseline demographic and disease characteristics were balanced across arms, as expected under stratified randomization. Binary efficacy endpoints were analysed by non-responder imputation, whereby patients with missing Week 12 status, or who discontinued or used prohibited rescue medication, were counted as non-responders. The continuous modified Mayo change was analysed within a mixed-model-for-repeated-measures (MMRM)/ANCOVA framework yielding least-squares (LS) means, which underlies the adjusted estimates tabulated below.

The integrated efficacy evidence for TILA-278 in Ulcerative Colitis (moderate-to-severe) rests on TILA278-201. Primary endpoint Clinical remission (modified Mayo) at Week 12:

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)	—

Adjusted magnitude of effect (continuous modified Mayo change). The table above summarises the LS-mean reduction from baseline in the modified Mayo score at Week 12. TILA-278 produced dose-ordered reductions of -3.36 (High) and -2.76 (Low) points versus -1.00 for placebo, corresponding to placebo-adjusted treatment effects of -2.36 (95% CI -2.49, -2.23) and -1.77 (95% CI -1.90, -1.64) points, respectively. Both were statistically significant (p = 0.0000; i.e., p < 0.0001), with confidence intervals excluding the null by a wide margin. The magnitude of the higher-dose reduction exceeds the change generally regarded as clinically meaningful on the modified Mayo instrument.

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)	—

Primary endpoint interpretation (clinical remission). Clinical remission was defined as a modified Mayo score <= 2 with no individual subscore > 1. At Week 12, remission was achieved by 37.3% (106/284) of High, 16.2% (46/283) of Low, and 0.7% (2/273) of placebo patients under non-responder imputation. The placebo-adjusted risk differences were 36.6 percentage points (95% CI 30.9, 42.3) for High and 15.5 percentage points (95% CI 11.1, 19.9) for Low, both p = 0.0000. The near-absent placebo remission rate (0.7%) reflects the stringency of the composite definition and its objective endoscopic component, and it sharpens the interpretability of the between-group differences.

Endoscopic improvement (key secondary). Consistent with the IL-22R-agonist mucosal-healing rationale, centrally-read endoscopic improvement showed the same dose-ordered pattern at Week 12:

Arm	N	Endoscopic improvement	Point difference vs placebo
TILA-278 High	284	48.9%	+42.7 pp
TILA-278 Low	283	27.9%	+21.7 pp
Placebo	273	6.2%	— (reference)

The alignment of a composite clinical-remission benefit with an objective endoscopic-healing benefit is the pattern expected of the dual mechanism and strengthens the inference that the effect reflects genuine mucosal disease modification rather than symptomatic masking.

Dose-response. Across the primary endpoint, the continuous modified Mayo change, and endoscopic improvement, responses were monotonically ordered High > Low > placebo. The higher dose approximately doubled the remission rate relative to the lower dose (37.3% vs 16.2%) and yielded a larger LS-mean reduction (-3.36 vs -2.76). A coherent dose-response across biologically related endpoints supports a causal, exposure-driven effect and informs dose selection for confirmatory study.

Subgroup consistency. The direction and dose-ordering of the primary treatment effect were consistent across the prespecified stratification factors and the major demographic and disease subgroups, including baseline severity and prior advanced-therapy exposure; no subgroup showed a reversal of benefit. Given the Phase 2b sample size, subgroup analyses are interpreted as supportive of homogeneity of effect rather than as independently powered comparisons.

Estimand, missing-data handling, and sensitivity analyses. The primary estimand targeted the composite (treatment-policy) difference in clinical remission at Week 12, with treatment discontinuation, prohibited rescue medication, and missing endoscopy handled as non-response — a conservative approach preferred for UC induction. The continuous endpoint used MMRM under a missing-at-random assumption. The concordance between the conservative binary (non-responder imputation) analysis and the model-based continuous analysis, together with the wide margins by which the confidence intervals exclude the null, indicates that the efficacy conclusions are robust to the missing-data framework.

Exposure-response and pharmacokinetic considerations. TILA-278 displays target-mediated drug disposition characteristic of antibodies directed at expressed targets, whereby binding to TL1A and IL-22R contributes a saturable clearance component at lower concentrations. The dose-ordered efficacy (High > Low) is consistent with an ascending portion of the exposure-response relationship over the studied dose range and supports selection of a dose that maintains target engagement across the dosing interval in confirmatory studies.

Immunogenicity and impact on efficacy. As an immunomodulatory therapeutic protein, TILA-278 carries an inherent potential for anti-drug antibody formation; ADA and, where relevant, neutralising-antibody status were monitored and evaluated for any association with reduced exposure or attenuated response. The robust, dose-ordered efficacy observed over the 12-week induction period indicates that immunogenicity did not materially undermine the treatment effect in this study; ADA impact on durability of response will continue to be characterised in longer-term maintenance evaluation.

Conclusion. In moderate-to-severe UC, TILA-278 demonstrated a statistically significant, dose-ordered, and clinically meaningful induction benefit at Week 12 across the primary clinical-remission endpoint (37.3% High, 16.2% Low, 0.7% placebo) and the key secondary continuous and endoscopic endpoints, with an internally consistent mechanistic signature of inflammatory control coupled to mucosal healing. These integrated results establish proof of efficacy for the bispecific anti-TL1A × IL-22R approach and provide the dose-response basis for confirmatory Phase 3 development. Effects were dose-ordered and consistent across the analysed populations, supporting a clinically meaningful benefit. ICH M4E(R2) §5.3.5.3.