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Integrated Summary of Safety (TILA-278)

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

Integrated Summary of Safety — TILA-278

Composition and scope of the integrated safety database

TILA-278 is a humanized IgG1 bispecific monoclonal antibody produced by recombinant Chinese hamster ovary (CHO) cell culture and administered by subcutaneous injection. One binding arm antagonizes TNF-like ligand 1A (TL1A), attenuating the pro-inflammatory and pro-fibrotic TL1A–DR3 axis, while the second arm acts as an agonist at the interleukin-22 receptor (IL-22R) to drive intestinal epithelial restitution and mucosal barrier repair. The dual mechanism is intended to couple down-regulation of mucosal inflammation with active epithelial healing in moderate-to-severe ulcerative colitis, and it shapes the categories of adverse event given prospective scrutiny below.

The integrated safety database for TILA-278 derives from TILA278-201 (safety set).

TILA278-201 was a Phase 2b, randomized, double-blind, placebo-controlled induction study that assigned subjects 1:1:1 to two subcutaneous dose regimens (High and Low) or placebo over a 12-week induction period. The safety set comprises all randomized subjects who received at least one dose of study drug (TILA-278 High 299, TILA-278 Low 300, placebo 301), and it is the basis for every summary in this section. Treatment-emergent adverse events (TEAEs) were defined as events with onset or worsening on or after the first dose; events were coded in MedDRA and tabulated by system organ class and preferred term, with maximum severity and investigator-assessed causality captured at the subject level. Safety comparisons are descriptive and were not subject to formal multiplicity control.

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

Extent of exposure and overall adverse event profile

All 900 randomized subjects contributed to the safety set across the 12-week induction period, with comparable planned subcutaneous exposure in the two active arms. The overall burden of treatment-emergent adverse events was similar across the three arms and showed no dose-dependent increase: at least one TEAE was reported in 109/299 (36.5%) subjects on TILA-278 High, 131/300 (43.7%) on TILA-278 Low, and 130/301 (43.2%) on placebo. The majority of events were mild or moderate in intensity and did not require dose interruption. Serious adverse events were infrequent and numerically balanced against placebo (High 3/299 [1.0%], Low 0/300, placebo 4/301 [1.3%]). Adverse events leading to discontinuation were more frequent on placebo (29/301, 9.6%) than on either active regimen (High 17/299, 5.7%; Low 17/300, 5.7%), consistent with the expected worsening of colitis in subjects not receiving active therapy. Three deaths occurred during the study (High 2, Low 0, placebo 1); each fatal event was reviewed individually by the investigator and the sponsor, and the small absolute numbers together with their distribution across arms did not indicate a causal relationship to study treatment.

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

Interpretation of the common-event profile

The most frequently reported preferred terms were consistent with the underlying ulcerative colitis population and with the monoclonal antibody class. Worsening of ulcerative colitis was reported roughly two to three times as often on placebo (35/301, 11.6%) as on TILA-278 High (13/299, 4.3%) or Low (19/300, 6.3%), in keeping with the intended anti-inflammatory effect of TL1A antagonism and IL-22R–mediated mucosal healing. Anaemia, a common consequence of active colitis, was reported across all arms (High 21/299, 7.0%; Low 17/300, 5.7%; placebo 28/301, 9.3%) without an active-arm excess. Nasopharyngitis, upper respiratory tract infection, headache, and arthralgia occurred at broadly comparable frequencies without a clear dose relationship; the numerically higher nasopharyngitis count in the Low arm (35/300, 11.7%) was not accompanied by any increase in serious or severe infection and is not interpreted as a dose-related signal.

Adverse events of special interest

In light of the immunomodulatory mechanism, events were monitored within prospectively defined categories:

• Infections. Because TL1A antagonism dampens mucosal inflammatory signaling while IL-22 biology contributes to antimicrobial peptide production and epithelial defense, serious and opportunistic infections were monitored throughout induction. No opportunistic infections and no imbalance in serious infection were observed; reported infections were predominantly non-serious upper respiratory events.
• Injection-site reactions and hypersensitivity. As a subcutaneously administered antibody, TILA-278 was evaluated for local injection-site reactions and for immediate and delayed systemic hypersensitivity. Such events were infrequent, non-serious, and did not produce a pattern of discontinuation.
• Hepatic events. Given the proliferative and cytoprotective roles of IL-22 signaling in epithelial and hepatic tissue, hepatic laboratory parameters were reviewed; no pattern of drug-induced transaminase elevation meeting Hy's law criteria was identified.
• Malignancy. Sustained IL-22R agonism is a theoretical long-term consideration for epithelial proliferation. No malignant events were anticipated or observed over the 12-week induction period; this category remains a focus of longer-term follow-up.
• Haematological events. Anaemia and related parameters were tracked in view of the disease background and showed no active-arm safety signal.

Laboratory evaluations and vital signs

Haematology, serum chemistry (including hepatic and renal parameters), and vital signs were assessed at scheduled visits. Observed shifts were generally consistent with the underlying disease and its response to therapy, with no clinically meaningful treatment-related trend. Consistent with the monoclonal antibody modality, cardiac electrophysiology assessment beyond routine safety monitoring was not warranted and no dedicated QT evaluation was required.

Immunogenicity and exposure considerations

TILA-278 exhibits target-mediated drug disposition, whereby binding to TL1A and to IL-22R contributes to non-linear clearance at lower concentrations; this behavior is accounted for in the population pharmacokinetic characterization and informs interpretation of exposure-related safety. Immunogenicity was assessed with a validated tiered strategy (screening, confirmatory, and titer determination, with a cell-based neutralizing-antibody assay). Given the bispecific format, anti-drug antibody responses were evaluated for reactivity against each binding domain. Treatment-emergent and treatment-boosted anti-drug antibodies, and any neutralizing responses, were correlated with exposure and with adverse-event occurrence to assess potential impact on pharmacokinetics, efficacy, and safety.

Nonclinical and product-quality context

The clinical safety profile is supported by a nonclinical program appropriate to a recombinant monoclonal antibody, with the cynomolgus monkey as the sole pharmacologically relevant toxicology species and study design following ICH S6(R1). Consistent with the modality, genotoxicity, carcinogenicity, hERG, and thorough-QT studies were not warranted. Product quality and comparability for the CHO-derived molecule are governed by ICH Q5A(R2) for viral safety, Q5C for stability, and Q6B for specifications and analytical characterization, with downstream purification incorporating Protein A capture followed by polishing steps; the product is the subject of a Biologics License Application under 21 CFR Part 601.

Adverse events were consistent with the bispecific monoclonal antibody class; serious events were infrequent. Immunogenicity: Anti-drug antibody (binding and neutralising) assessment is integral; immunogenicity may affect exposure and is characterised with a tiered validated assay strategy. ICH M4E(R2) §5.3.5.3.