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

---

Module 1 (EU) — Summary of Product Characteristics (TILA-278)

Document ID: M1-EU
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): QRD / 2001/83/EC

EU Summary of Product Characteristics (SmPC) — TILA-278

TILA-278 is a recombinant humanised bispecific immunoglobulin G1 (IgG1) monoclonal antibody produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology. One antigen-binding arm is an antagonist of TNF-like ligand 1A (TL1A; TNFSF15); the second arm is an agonist of the interleukin-22 receptor (IL-22R). The information below is presented under the Quality Review of Documents (QRD) headings applicable to this application.

4.1 Therapeutic indications. TILA-278 is indicated for the treatment of adult patients with moderately to severely active Ulcerative Colitis who have had an inadequate response, loss of response, or intolerance to either conventional therapy (corticosteroids and immunomodulators) or a biologic or targeted advanced therapy. Efficacy has been characterised in the induction of clinical remission; treatment should be initiated and supervised by a physician experienced in the diagnosis and management of Ulcerative Colitis.

4.2 Posology and method of administration.

Posology. TILA-278 is administered by subcutaneous injection according to the approved induction regimen. Two dose levels were evaluated in the induction programme; the recommended posology reflects the approved regimen and should not be exceeded. Continuation beyond the induction period should be based on the individual patient's clinical response, and treatment should be reconsidered in patients who show no evidence of therapeutic benefit by the end of induction.

Missed dose. If a scheduled dose is missed, it should be administered as soon as possible, after which dosing should resume at the regular interval; two doses should not be administered to compensate for a missed dose.

Special populations. No dedicated dose adjustment is required in elderly patients; clinical experience in patients aged 65 years and over is more limited than in younger adults. No formal studies have been conducted in renal or hepatic impairment. As an intact IgG monoclonal antibody, TILA-278 is eliminated by catabolism to peptides and amino acids rather than by renal excretion or hepatic metabolism, and no clinically meaningful effect of renal or hepatic impairment on exposure is expected; no dose adjustment is anticipated on this basis. The safety and efficacy of TILA-278 in children and adolescents below 18 years of age have not yet been established; no data are available.

Method of administration. TILA-278 is for subcutaneous use. Injection sites should be rotated among the abdomen, thigh, and upper arm, avoiding areas where the skin is tender, bruised, erythematous, indurated, or affected by active disease. After appropriate training in subcutaneous injection technique, a patient may self-inject, or a caregiver may administer the product, if the physician judges this appropriate. The product should be inspected visually before use and should not be administered if particulate matter or discolouration is observed.

4.3 Contraindications. Known serious hypersensitivity to the active substance or to any of the excipients. Active, clinically serious infection, including active tuberculosis; treatment must not be initiated in patients with an active serious infection until the infection is controlled. Consistent with the mechanism of action, screening for latent tuberculosis and for hepatitis B virus infection prior to initiation is recommended in accordance with local clinical guidance.

5.1 Pharmacodynamic properties.

Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants; ATC code: not yet assigned.

Mechanism of action. TILA-278 is a bispecific monoclonal antibody that simultaneously modulates two non-redundant pathways in the inflamed intestinal mucosa. Through its anti-TL1A arm it antagonises the pro-inflammatory cytokine TL1A (TNFSF15), blocking engagement of its receptor DR3 (death receptor 3; TNFRSF25) on effector T cells and innate lymphoid cells. TL1A–DR3 signalling amplifies Th1/Th17-type effector responses and promotes activation of mucosal fibroblasts; its blockade therefore confers both an anti-inflammatory and an anti-fibrotic effect. Through its IL-22R agonist arm, TILA-278 engages the IL-22 receptor complex (IL-22RA1/IL-10RB) expressed on intestinal epithelial cells, driving epithelial proliferation, mucus and antimicrobial-peptide production, and restoration of barrier integrity—processes that underlie mucosal healing. Co-localisation of TL1A antagonism with IL-22R agonism in a single molecule is intended to couple suppression of the inflammatory/fibrotic drive with active promotion of epithelial and mucosal repair.

Pharmacodynamic effects. The dual mechanism is expected to translate into reduction of mucosal inflammation together with endoscopic and histological improvement of the colonic epithelium, consistent with the clinical endpoints evaluated in the induction programme.

Clinical efficacy. Pivotal efficacy is derived from Study TILA278-201, a Phase 2b, randomised, double-blind, placebo-controlled, parallel-group induction study evaluating two subcutaneous dose levels of TILA-278 (High and Low) versus placebo, randomised 1:1:1, over a 12-week induction period in adults with moderately to severely active Ulcerative Colitis. Of 1700 patients screened, 900 were randomised (299 to TILA-278 High, 300 to TILA-278 Low, and 301 to placebo); the full analysis set comprised 840 patients (284 High, 283 Low, 273 placebo). The primary endpoint was clinical remission at Week 12, defined as a modified Mayo score of 2 or less with no individual subscore greater than 1. Change in modified Mayo score and endoscopic improvement were assessed as key secondary endpoints.

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, 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)	—

Both dose levels separated from placebo on the primary endpoint of clinical remission at Week 12, with a dose-ordered response (37.3% High, 16.2% Low, 0.7% placebo). Endoscopic improvement (Mayo endoscopic subscore of 1 or less) at Week 12 was achieved by 48.9%, 27.9%, and 6.2% of patients in the TILA-278 High, TILA-278 Low, and placebo arms, respectively, supporting the mucosal-healing component of the mechanism of action. The LS-mean reduction in modified Mayo score of -3.36 (High) and -2.76 (Low) versus -1.00 (placebo), corresponding to placebo-adjusted differences of -2.36 and -1.77, was consistent with the responder analysis.

Immunogenicity. As with therapeutic proteins in general, administration of TILA-278 may be associated with the development of anti-drug antibodies. The clinical relevance of anti-drug antibody formation—including potential effects on exposure, on efficacy, and on hypersensitivity or injection-site reactions—is being characterised, and the assay for detecting anti-drug antibodies is dependent on several methodological factors, so that comparisons of the incidence of antibodies across products may be misleading.

5.2 Pharmacokinetic properties. Following subcutaneous administration, TILA-278 is absorbed with a time course and bioavailability typical of an IgG1 monoclonal antibody. Distribution is largely confined to the plasma and interstitial fluid, consistent with the limited distribution volume expected for an intact immunoglobulin. TILA-278 is not metabolised by cytochrome P450 enzymes; in common with endogenous IgG it is degraded by proteolytic catabolism into small peptides and amino acids, and its persistence in the circulation is prolonged by neonatal Fc receptor (FcRn)-mediated recycling. Elimination comprises a linear, non-saturable catabolic pathway together with a saturable, target-mediated component: engagement of TL1A and of the IL-22 receptor produces target-mediated drug disposition (TMDD), giving rise to non-linear pharmacokinetics with more-than-dose-proportional exposure at low concentrations as the target-mediated route saturates, approaching linearity at the higher concentrations achieved on therapeutic dosing. Body weight is an expected covariate on exposure; based on the mechanism of elimination, renal or hepatic impairment, age, and sex are not anticipated to have clinically meaningful effects on the pharmacokinetics, and anti-drug antibodies may increase clearance in a subset of patients. The pharmacokinetics of TILA-278 have been characterised nonclinically in the cynomolgus monkey, the pharmacologically relevant species for both binding arms. Classical small-molecule ADME assessment (mass balance, cytochrome P450 and drug-transporter studies) is not applicable to an intact IgG.

QRD template; Directive 2001/83/EC.