📚 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) — IMPD Summary (TILA-278)

Document ID: M1-IMPD
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): CTR 536/2014

Investigational Medicinal Product Dossier (IMPD) — TILA-278

EU clinical-trial dossier for TILA-278 (bispecific monoclonal antibody). Summarises the quality (S/P), non-clinical, and clinical data supporting the trial in Ulcerative Colitis (moderate-to-severe), cross-referencing Modules 3-5. Directive 2001/20/EC; CTR 536/2014; ICH.

---

Scope, structure and applicable guidance

This Investigational Medicinal Product Dossier (IMPD) provides the integrated quality, non-clinical and clinical (human-experience) information supporting the clinical use of TILA-278 in adults with moderately-to-severely active ulcerative colitis (UC). It is organised in accordance with the EudraLex Volume 10 IMPD structure and the Guideline on the requirements for the chemical and pharmaceutical quality documentation concerning investigational medicinal products in clinical trials (EMA/CHMP/QWP/545525/2017). The dossier is submitted under Regulation (EU) No 536/2014 (Clinical Trials Regulation); the underlying data packages are held in CTD format and are cross-referenced to Modules 3 (Quality), 4 (Non-clinical) and 5 (Clinical).

Because TILA-278 is a recombinant biotechnology-derived medicinal product, the following ICH guidance is applicable and has been followed: ICH Q5A(R2) (viral safety of biotechnology products), ICH Q5C (stability of biotechnology/biological products), ICH Q5D/Q5E (cell substrates; comparability), ICH Q6B (specifications for biotechnological/biological products), ICH Q8(R2)/Q11 (development and manufacture of the active substance), and ICH S6(R1) (preclinical safety evaluation of biotechnology-derived pharmaceuticals). The QT/safety-pharmacology waiver rationale is consistent with ICH S6(R1), S7A/S7B and E14 for a monoclonal antibody.

Investigational medicinal product — identity and mechanism of action

TILA-278 is a recombinant humanised immunoglobulin G1 (IgG1, κ) bispecific monoclonal antibody produced in a Chinese Hamster Ovary (CHO) cell line and administered by the subcutaneous (SC) route. The molecule combines two independent, complementary activities on a single antibody framework:

• Anti-TL1A arm (antagonist): high-affinity neutralisation of human TL1A (TNFSF15), blocking TL1A engagement of its receptor DR3 (TNFRSF25). TL1A blockade attenuates T-cell– and innate-lymphoid-cell–driven mucosal inflammation and has an established anti-inflammatory and anti-fibrotic rationale in inflammatory bowel disease.
• IL-22R arm (agonist): engagement and agonism of the IL-22 receptor alpha-1 chain (IL-22RA1), driving IL-22RA1/IL-10RB–JAK1/TYK2–STAT3 signalling in intestinal epithelial cells to promote epithelial regeneration, antimicrobial peptide production and mucosal (barrier) healing.

The dual mechanism is intended to couple suppression of the inflammatory drive (TL1A antagonism) with active restoration of the epithelial barrier (IL-22R agonism), addressing both the inflammatory and the reparative dimensions of UC. The Fc region is effector-attenuated so that the molecule neutralises a cytokine and agonises a receptor without eliciting Fcγ-receptor– or complement-mediated effector function, while retaining FcRn-mediated recycling to support an SC dosing interval. The drug product is a preservative-free, histidine-buffered solution at a nominal 150 mg/mL protein concentration presented in a single-use prefilled syringe and prefilled pen (autoinjector) for SC administration; the induction posology and the two active dose levels evaluated clinically are summarised in Section 2.3.

---

2.1 Quality data (Modules 3.2.S / 3.2.P)

2.1.S Drug substance

The active substance is a humanised IgG1(κ) bispecific antibody assembled as an asymmetric, monovalent-per-target (1 + 1) full-length IgG1. Correct heavy-chain heterodimerisation and cognate light-chain pairing are enforced by established antibody-engineering approaches, and the CH2 domain carries a single conserved N-linked glycosylation site. The active substance is manufactured by fed-batch CHO cell culture followed by a platform purification train: Protein A affinity capture, orthogonal polishing chromatography (cation- and anion-exchange and/or mixed-mode steps, the latter also depleting format-specific product-related species such as homodimer/half-antibody/mispaired species), dedicated low-pH viral inactivation, nanofiltration for size-based virus removal, and ultrafiltration/diafiltration into the final formulation buffer. Cell banking (master and working cell banks) and viral safety are controlled per ICH Q5A(R2)/Q5D, with genetic stability demonstrated to and beyond the limit of in vitro cell age (ICH Q5B).

Characterisation follows ICH Q6B using orthogonal state-of-the-art methods (intact/subunit mass spectrometry, peptide mapping, disulfide mapping, released N-glycan analysis, icIEF/CEX for charge heterogeneity, SE-HPLC and reduced/non-reduced CE-SDS for size heterogeneity, and higher-order-structure methods), with particular emphasis on the attributes specific to a bispecific format — correct chain pairing, control of mispaired/homodimeric species, and independent functionality of both arms. Potency is measured by two orthogonal cell-based bioassays that interrogate the two mechanisms of action: a TL1A-neutralisation reporter assay (anti-TL1A arm) and a STAT3 reporter/pSTAT3 assay for IL-22RA1 agonism (IL-22R arm); a dual-binding assay confirms simultaneous engagement of both targets by a single molecule. The drug-substance specification controls identity, size and charge purity, glycosylation, both potencies, and process-related impurities (host-cell protein by anti-CHO ELISA, residual host-cell DNA by CHO-specific qPCR, residual Protein A, endotoxin and bioburden). Stability is established under ICH Q5C using stability-indicating methods; aggregation, fragmentation and charge-variant shifts are the principal degradation pathways, tracked by both potency assays.

2.1.P Investigational medicinal product (drug product)

The investigational medicinal product is a sterile, preservative-free SC solution formulated in an L-histidine/histidine-hydrochloride buffer with sucrose (stabiliser/tonicity) and polysorbate 80 (surfactant), filled into a single-use glass prefilled syringe and an autoinjector (prefilled pen) presentation and, for early-phase and comparative work, provided with a matching placebo to preserve the double blind. Drug-product manufacture comprises compounding, sterile (0.2 µm) filtration and aseptic fill/finish, with in-process and release controls for appearance, protein content, pH, osmolality, sub-visible and visible particulate matter, extractable volume/deliverable dose, container-closure integrity, sterility and endotoxin, alongside the size, charge and dual-potency attributes carried from the active-substance panel. Drug-product stability is evaluated under ICH Q5C long-term, accelerated and stressed conditions, including in-use and device-functionality (delivery) testing, and photostability per ICH Q1B; the product is protected from light. Comparability across the clinical and toxicology lots and across manufacturing changes is assessed per ICH Q5E, confirming that the material used in the non-clinical programme and in study TILA278-201 is representative.

2.1.A Adventitious-agent safety and appendices

Adventitious-agent safety is assured by control of the cell substrate and raw materials, by testing of unprocessed bulk, and by the demonstrated viral clearance capacity of the orthogonal downstream process (dedicated low-pH inactivation plus size- and charge-based removal steps), evaluated in scaled-down qualified models against relevant and model viruses per ICH Q5A(R2). Cell-culture media and feeds are chemically defined and animal-component-free; materials of biological origin, where used, comply with the TSE/BSE requirements (EMA/410/01 rev. 3; Ph. Eur. 5.2.8). No materials of human origin are used, and the finished product neither contains nor consists of GMOs.

2.2 Non-clinical pharmacology and toxicology (Module 4)

The non-clinical package is designed in accordance with ICH S6(R1) for a biotechnology-derived product and reflects the species-restricted pharmacology of the two targets.

2.2.1 Primary and secondary pharmacology

Primary pharmacology confirms the intended dual mechanism in vitro: high-affinity, specific binding to human TL1A with neutralisation of TL1A/DR3 signalling, and binding to human IL-22RA1 with agonist induction of STAT3-dependent epithelial responses, together with confirmation that a single molecule engages both targets simultaneously. In vivo activity consistent with anti-inflammatory (TL1A antagonism) and epithelial/mucosal-healing (IL-22R agonism) effects supports the therapeutic hypothesis in UC. Species cross-reactivity screening establishes that the cynomolgus monkey is the sole pharmacologically relevant toxicology species (human-comparable engagement of both targets); rodents are not pharmacologically relevant, which governs the toxicology design below.

2.2.2 Safety pharmacology

Consistent with ICH S6(R1) and S7A/S7B, no standalone safety-pharmacology studies and no in vitro hERG (ion-channel) or in vivo thorough-QT assessment were conducted, as these are not warranted for a large, target-specific monoclonal antibody that does not distribute intracellularly or interact with cardiac ion channels. Cardiovascular, respiratory and central-nervous-system safety-pharmacology endpoints were instead incorporated into the repeat-dose toxicology study in the cynomolgus monkey (including electrocardiography, blood-pressure/heart-rate, respiratory and clinical/neurological observations).

2.2.3 Pharmacokinetics and TMDD

Non-clinical pharmacokinetics in the cynomolgus monkey characterise SC bioavailability and disposition and show target-mediated drug disposition (TMDD): non-linear, dose-dependent clearance at lower exposures that becomes approximately linear once target is saturated, as expected for an antibody directed at membrane/soluble targets. These data, together with the two-target engagement, informed the human dose-range and the exposure-margin assessment. Anti-drug-antibody (ADA) monitoring was integrated into the toxicology studies to contextualise any exposure changes.

2.2.4 Toxicology

The pivotal toxicology programme comprises repeat-dose SC toxicity studies in the cynomolgus monkey (the only relevant species), with toxicokinetics, immunophenotyping and T-cell-dependent antibody-response assessment, local tolerance at the injection site, tissue cross-reactivity, and monitoring of immunogenicity (ADA). Reproductive and developmental toxicity is addressed within the S6(R1) framework using the non-human-primate model (e.g., an enhanced pre-/post-natal development design) as appropriate to support the intended population. Safety margins are expressed as multiples of the clinical exposure (AUC/C_max) at the studied dose levels.

2.2.5 Non-clinical studies not conducted and justification

Genotoxicity and carcinogenicity studies were not conducted and are not warranted for this monoclonal antibody: an IgG antibody does not interact directly with DNA or other chromosomal material, and standard genotoxicity assays and lifetime rodent bioassays are not scientifically meaningful or feasible for a large protein that is pharmacologically active only in primates (ICH S6(R1)). As noted in Section 2.2.2, dedicated hERG and thorough-QT studies were likewise not performed. The overall non-clinical strategy is proportionate to the biotechnology-derived nature of the product and to the species restriction of its pharmacology.

2.3 Previous clinical trial and human experience data (Module 5)

2.3.1 Clinical pharmacology (Phase 1 first-in-human experience)

First-in-human single-ascending-dose and multiple-ascending-dose experience characterised the safety, tolerability, pharmacokinetics and immunogenicity of TILA-278 by the SC route. The pharmacokinetic profile is consistent with the non-clinical prediction, showing TMDD-type non-linearity at lower exposures and an SC absorption/half-life profile supporting the induction dosing interval; these data underpinned the dose selection for the Phase 2b study.

2.3.2 Phase 2b induction study TILA278-201

Study TILA278-201 is a Phase 2b, randomised, double-blind, placebo-controlled, parallel-group, 12-week induction study in adults with moderately-to-severely active UC, with 1:1:1 randomisation to TILA-278 High-dose, TILA-278 Low-dose, or placebo (SC). A total of 1700 subjects were screened and 900 were randomised (299 High / 300 Low / 301 Placebo); the Full Analysis Set (FAS) comprised 840 subjects (284 / 283 / 273).

The primary endpoint was clinical remission (modified Mayo score ≤ 2, with no individual subscore > 1) at Week 12. The primary endpoint was met, with a clear, dose-ordered separation from placebo, and was supported by the key secondary endpoints (modified Mayo LS-mean change from baseline and endoscopic improvement).

Endpoint at Week 12 (FAS)	TILA-278 High (N=284)	TILA-278 Low (N=283)	Placebo (N=273)
Clinical remission (mMayo ≤ 2, no subscore > 1)	37.3% (106/284)	16.2% (46/283)	0.7% (2/273)
Modified Mayo — LS-mean change from baseline	−3.36	−2.76	−1.00
Difference vs placebo (LS-mean)	−2.36	−1.77	—
Endoscopic improvement	48.9%	27.9%	6.2%

The LS-mean difference from placebo in modified Mayo change was −2.36 (95% CI −2.49, −2.23; p<0.0001) for High-dose and −1.77 (95% CI −1.90, −1.64; p<0.0001) for Low-dose. The consistency of the treatment effect across the primary remission endpoint, the continuous modified Mayo change, and the endoscopic-improvement endpoint provides internally coherent, mechanism-consistent evidence of induction efficacy.

2.3.3 Immunogenicity

Immunogenicity is a relevant consideration for this SC-administered antibody and is evaluated with a tiered strategy (screening, confirmatory and titre assays) with assessment of neutralising antibodies and of any relationship between ADA, exposure, efficacy and safety. Immunogenicity monitoring is integrated into the clinical programme and is reflected in the ongoing benefit-risk characterisation and the risk-management strategy.

2.3.4 Clinical safety

In study TILA278-201, treatment-emergent adverse events were reported in 109 / 131 / 130 subjects (High / Low / Placebo). Serious adverse events occurred in 3 / 0 / 4 subjects and deaths in 2 / 0 / 1 subjects, all assessed as unrelated to study drug; discontinuations were 17 / 17 / 29, with placebo discontinuations predominantly for lack of efficacy. Injection-site reactions were the principal drug-attributable finding and were more frequent with active SC treatment than with placebo. No new or unexpected safety signal emerged over the 12-week induction period. The most relevant risks for continued clinical use — injection-site reactions (identified), and serious/opportunistic infections, hypersensitivity/immunogenicity-related reactions and the theoretical class consideration of malignancy for immunomodulators (potential) — are managed through routine and, where applicable, additional pharmacovigilance and risk-minimisation measures.

2.4 Overall benefit-risk assessment

The available quality, non-clinical and clinical data support the continued clinical investigation of TILA-278 in moderately-to-severely active UC. The quality package establishes a well-characterised, consistently manufactured CHO-derived bispecific IgG1 with orthogonal control of both mechanisms of action and a viral-safety and impurity-control strategy appropriate to a biotechnology-derived product. The non-clinical package, conducted in the sole pharmacologically relevant species (cynomolgus monkey) per ICH S6(R1), supports the intended clinical exposures with adequate margins and appropriately omits genotoxicity, carcinogenicity, hERG and thorough-QT studies, which are not warranted for a monoclonal antibody. Clinically, the pivotal Phase 2b induction study met its primary endpoint with a dose-ordered clinical-remission rate (37.3% High, 16.2% Low, 0.7% placebo) and consistent secondary-endpoint separation, against a safety profile in which injection-site reactions were the principal drug-attributable finding and no serious drug-related events or unexpected signals were identified over the induction period. The dual mechanism — TL1A antagonism (anti-inflammatory/anti-fibrotic) combined with IL-22R agonism (epithelial/mucosal healing) — provides a biologically coherent rationale for the observed effect. On the totality of the evidence, the benefit-risk balance supports the planned clinical use, with residual uncertainties (long-term efficacy and safety beyond induction, immunogenicity impact, use in special populations) addressed through the ongoing development programme and risk-management plan.

Reference documents and cross-references

• Quality (Module 3): 3.2.S Drug Substance; 3.2.P Drug Product; 3.2.A Appendices (adventitious-agent safety, facilities); 3.2.R Regional information; analytical methods validation and control strategy.
• Non-clinical (Module 4): 4.2.1 Pharmacology; 4.2.2 Pharmacokinetics; 4.2.3 Toxicology study reports; non-clinical overview and summaries (Modules 2.4/2.6).
• Clinical (Module 5): first-in-human SAD/MAD study reports; TILA278-201 clinical study report and synopsis; immunogenicity summary; clinical overview and summaries (Modules 2.5/2.7); Investigator's Brochure.
• Applicable guidance: Regulation (EU) No 536/2014; Directive 2001/20/EC; EudraLex Volume 10 and EMA/CHMP/QWP/545525/2017 (IMPD quality); ICH Q5A(R2), Q5B, Q5C, Q5D, Q5E, Q6B, Q8(R2), Q11; ICH S6(R1), S7A/S7B and E14 (QT waiver rationale).