Module 2.5.6 — Benefit–Risk Assessment (TILA-278)
Document ID: M2.5.6 Version: 1.0 Change History: 1.0 — Initial issue. Standard(s): ICH M4E(R2)
2.5.6 Benefit–Risk Assessment
Therapeutic context
Ulcerative Colitis (moderate-to-severe) carries substantial morbidity, and a proportion of patients do not achieve or sustain response on available therapies. TILA-278 addresses this need via TL1A antagonism (anti-inflammatory/anti-fibrotic) + IL-22R agonism (epithelial healing).
Benefits
| 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) | — |
Responder analysis — Clinical remission (Mayo <= 2)
| Arm | N | Responders | Rate | Risk diff vs placebo (95% CI, %) | p |
|---|---|---|---|---|---|
| TILA-278 High | 284 | 106 | 37.3% | 36.6% (30.9, 42.3) | 0.0000 |
| TILA-278 Low | 283 | 46 | 16.2% | 15.5% (11.1, 19.9) | 0.0000 |
| Placebo | 273 | 2 | 0.7% | — (reference) | — |
The active arms produced a dose-ordered, statistically significant, and clinically meaningful improvement in Modified Mayo Score versus placebo at Week 12.
Risks
| 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 |
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 |
Adverse events were consistent with the compound class; serious events and deaths were infrequent and without a dose-related pattern.
Conclusion
The benefit–risk balance is favourable and supports continued development into confirmatory studies.