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Signal Management Plan (TILA-278)

Document ID: SIGNAL-001
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): GVP IX

Signal Management Plan — TILA-278

Process for detecting, validating, prioritising, assessing, and acting on safety signals for TILA-278 across clinical and post-marketing sources, feeding the RMP and the reference safety information. Immunogenicity considerations: Anti-drug antibody (binding and neutralising) assessment is integral; immunogenicity may affect exposure and is characterised with a tiered validated assay strategy. GVP Module IX.

1. Purpose, scope and product context

This Signal Management Plan (SMP) defines the sponsor's end-to-end process for the continuous, proactive management of safety signals for TILA-278 (INN tilarudimab; ATC class L04AC), a recombinant humanised IgG1 bispecific monoclonal antibody produced by Chinese hamster ovary (CHO) cell culture and administered subcutaneously (SC) for the treatment of moderately-to-severely active ulcerative colitis (UC). The molecule delivers a single, dual pharmacology: one arm antagonises TL1A (TNFSF15), dampening TH1/TH17-driven inflammation and intestinal fibrosis, while the second arm agonises the interleukin-22 receptor (IL-22R), driving intestinal epithelial regeneration and mucosal-barrier repair. This mechanism-of-action is the organising principle for signal detection: TL1A antagonism directs vigilance toward the consequences of immunomodulation (serious and opportunistic infection), while IL-22R agonism directs specific long-term vigilance toward epithelial/colorectal proliferation and neoplasia. The plan is written in accordance with the principles of EU Good Pharmacovigilance Practices (GVP) Module IX (Signal management) and Module IX Addendum I (methodological aspects), and is consistent with ICH E2E and the structure of the pharmacovigilance plan in the Risk Management Plan (M1-RMP, EU RMP).

Scope. The SMP covers all safety data sources relevant to TILA-278 across its lifecycle. At the current development stage the clinical trial database is the dominant source; the plan is deliberately written to remain valid across the transition to the post-authorisation setting, at which point spontaneous reporting and quantitative disproportionality analysis become primary detection tools. Signals are managed for the medicinal product, its active substance and, where relevant, the device/presentation (pre-filled syringe and pre-filled pen for SC administration).

Regulatory basis for the product. TILA-278 is intended for a Biologics License Application under 21 CFR Part 601 (US) and equivalent marketing authorisation procedures in other regions. The quality, non-clinical and clinical framework applying to signal interpretation includes ICH Q5A(R2) (viral safety), Q5C (stability of biotechnological products), Q6B (specifications for biotechnological products), and S6(R1) (preclinical safety evaluation of biotechnology-derived pharmaceuticals). Consistent with ICH S6(R1), standard genotoxicity and rodent carcinogenicity bioassays are not part of the development paradigm for this monoclonal antibody, and — consistent with ICH S7B/E14 — a hERG assay and a thorough-QT study are not warranted for a monoclonal antibody with no expectation of direct cardiac ion-channel interaction. These study types therefore do not constitute signal sources; the theoretical long-term neoplasia question arising from chronic immunomodulation and IL-22R-mediated epithelial proliferation is instead managed as a clinical potential-risk signal (Section 9).

2. Governance, roles and responsibilities

Signal management is operated by a standing Safety Management/Signal Review Team that convenes on a defined periodicity and ad hoc when an emerging issue is identified. Accountabilities are summarised below.

Function	Responsibility in the signal management process
Qualified Person for Pharmacovigilance (QPPV) / global safety officer	Ultimate oversight and accountability for the pharmacovigilance system and for the conduct of signal management; assurance of regulatory notification and reporting
Safety physician(s) / medical safety lead	Medical review of individual case safety reports (ICSRs) and aggregate data; clinical validation, assessment and causality/expectedness judgement; authorship of signal evaluation reports
Pharmacovigilance / drug-safety scientists	Operation of the case-processing and detection workflow, aggregate data preparation, quantitative screening, maintenance of the signal tracking system
Biostatistics / epidemiology	Design and interpretation of quantitative signal-detection outputs (disproportionality and, once available, observed-versus-expected and cohort analyses), exposure denominators
Clinical pharmacology / bioanalytical	Interpretation of exposure–response, target-mediated drug disposition (TMDD) pharmacokinetics, and the immunogenicity (anti-drug antibody, ADA) dataset in relation to safety signals
Clinical development / study team and Data Safety Monitoring Board (DSMB)	Blinded and, where charter-permitted, unblinded review of accumulating clinical trial safety data; escalation of study-level safety findings
Regulatory affairs	Interface with competent authorities and, in the EU, with the Pharmacovigilance Risk Assessment Committee (PRAC); implementation of labelling and RMP changes arising from signals

The Signal Review Team documents its deliberations and decisions in the signal tracking system (Section 11) and escalates confirmed and emerging safety issues per the timelines in Section 12.

3. Data sources for signal detection

Signal detection draws on all sources of interpretable safety information. The relative weight of each source shifts across the lifecycle; the current database is dominated by the pivotal induction study.

Source	Description and current status
Interventional clinical trials	Pivotal Phase 2b induction study TILA278-201 (randomised, double-blind, placebo-controlled; 1700 screened, 900 randomised 1:1:1 to TILA-278 High / TILA-278 Low / placebo; safety set 299 / 300 / 301). Planned long-term controlled maintenance and open-label extension study TILA278-301 will extend the exposure base beyond the 12-week induction period.
Solicited sources / patient support and market-research programmes	To be captured for medically confirmed reports once such programmes exist post-authorisation; none contributing at present.
Spontaneous reports	Not yet applicable — TILA-278 is not authorised in any region and there is no post-marketing exposure at the data lock point. This source becomes primary after authorisation.
Regulatory safety databases	EudraVigilance (EU) and FAERS (US) monitoring and, once post-authorisation data accrue, the EudraVigilance Data Analysis System (EVDAS) electronic Reaction Monitoring Reports (eRMRs).
Scientific literature	Systematic and ongoing literature surveillance for TL1A-directed and IL-22/IL-22R-directed agents, bispecific IgG1 antibodies, and safety topics relevant to the UC population.
Non-clinical and clinical pharmacology	Cynomolgus monkey (the sole pharmacologically relevant toxicology species) repeat-dose findings; TMDD pharmacokinetics; the tiered immunogenicity/ADA dataset (Section 10).
Competent authority and partner information	Signals, requests and information exchanged with regulators, and any co-development/licensing-partner safety data under data-exchange agreements.

4. Signal detection methods

Signal detection combines qualitative medical review with quantitative statistical screening, with the balance determined by the maturity and type of the data.

Qualitative detection (primary at the current development stage).

• Ongoing medical review of individual serious and non-serious events, with particular attention to designated events of special interest (Section 9).
• Structured aggregate review of accumulating clinical trial data, including DSMB review of blinded/unblinded safety data and cumulative review at each Development Safety Update Report (DSUR) data lock point.
• Review of laboratory, vital-sign and exposure trends, injection-site tolerability, and events temporally or mechanistically linked to the dual pharmacology.
• Assessment of expectedness against the Reference Safety Information (RSI) in the current Investigator's Brochure during development, and against the Company Core Data Sheet / approved product information once authorised.

Quantitative detection (primary post-authorisation).

• Disproportionality analysis of spontaneous data using the proportional reporting ratio (PRR), reporting odds ratio (ROR) and Bayesian methods (e.g., the Multi-item Gamma Poisson Shrinker, EBGM), with statistics of disproportionate reporting reviewed in EVDAS eRMRs and FAERS.
• Conventional signalling thresholds (for example PRR ≥ 2 with χ² ≥ 4 and at least 3 cases) are applied as screening — not decision — criteria; every statistical flag is subject to medical review, and clinically important events are not dismissed for failing a numerical threshold.
• Where exposure denominators permit, observed-versus-expected and cohort analyses (including planned registry-based data, see the RMP pharmacovigilance plan) support quantitative evaluation of the pre-specified potential risks.

Because interventional exposure to date is limited to a 12-week induction period in an adult, predominantly < 65-year population, quantitative disproportionality is not yet informative; detection presently rests on qualitative aggregate clinical review and DSMB oversight. The methods above are stated now so that the transition to routine quantitative screening is seamless at first authorisation.

5. Signal validation

Each detected signal — whether arising from qualitative review, a statistical flag, the literature, or a regulatory source — is validated to determine whether the available evidence supports a new potentially causal association, or a new aspect of a known association, that warrants further analysis. Validation considers: the strength and consistency of the evidence; the clinical relevance and seriousness of the event; biological plausibility in the light of TL1A antagonism and IL-22R agonism; temporal relationship and, where relevant, dechallenge/rechallenge; exposure (including nonlinear TMDD behaviour) and ADA status; the background rate of the event in the moderate-to-severe UC population and its comorbidities; and the potential contribution of concomitant corticosteroids, immunomodulators and biologics. The validation outcome (validated / not validated / requires further information) and its rationale are recorded in the signal tracking system.

6. Signal prioritisation

Validated signals are prioritised to ensure that those with the greatest potential impact on patients and on the benefit-risk balance are handled first and, where necessary, outside the routine cycle. Prioritisation weighs: the seriousness, severity, reversibility and preventability of the event; the strength and novelty of the evidence; the size of the exposed and at-risk population; the potential for a change to the benefit-risk balance or to risk minimisation; and any public-health or vulnerable-population considerations (for example use in pregnancy, which is carried as missing information in the RMP). Signals meeting the criteria for an emerging safety issue are escalated immediately (Section 12) rather than awaiting the next periodic review.

7. Signal assessment

Prioritised signals undergo in-depth assessment integrating all relevant clinical, non-clinical, pharmacological and epidemiological data. For TILA-278, assessment routinely incorporates:

• The clinical trial safety database and the mechanism-informed events of special interest (Section 9).
• Exposure–response and PK context, including TMDD-driven nonlinearity and the effect of ADA on exposure, efficacy and safety (Section 10).
• Non-clinical findings from the cynomolgus monkey programme, recognising that no rodent carcinogenicity, genotoxicity, hERG or thorough-QT data exist or are expected for this modality; mechanistic (exaggerated-pharmacology) findings, rather than dedicated bioassays, inform the infection and neoplasia assessments.
• The background epidemiology of UC and its comorbidities (anaemia, thromboembolism, extra-intestinal manifestations, and the elevated long-term colorectal-cancer risk intrinsic to chronic colitis), to distinguish drug-attributable events from disease- and co-medication-related background.

The assessment concludes on whether the evidence confirms, refutes, or leaves open a causal association and whether the benefit-risk balance is affected. Assessment is documented in a signal evaluation report.

8. Recommendation for action and interface with risk minimisation

Each assessed signal yields a documented recommendation, which may include: no action with continued routine monitoring; a request for additional information; intensified/targeted data collection (including specific adverse-reaction follow-up questionnaires); an update to the RSI, Company Core Data Sheet or product information; a new or amended safety concern, additional pharmacovigilance activity or additional risk minimisation measure in the RMP; a change to study conduct or informed consent; or urgent safety measures and regulatory notification. Confirmed signals that establish a new identified or potential risk, or that alter the characterisation of an existing one, are reflected in the safety specification and the pharmacovigilance/risk-minimisation plans of the RMP, and are described in the next DSUR and, post-authorisation, the Periodic Benefit-Risk Evaluation Report (PBRER/PSUR).

9. Events and areas of special interest

A set of mechanism- and population-informed topics is subject to targeted, event-level review irrespective of statistical flags. These map directly onto the safety concerns of the RMP to keep signal management, the safety specification and risk minimisation aligned.

Topic of special interest	Mechanistic / clinical rationale	RMP alignment	Targeted detection approach
Injection-site reactions	Local reactogenicity intrinsic to SC biologic administration; the principal drug-attributable finding in TILA278-201 (more frequent on active arms, ~8–12% vs ~3% placebo, without a High-vs-Low gradient)	Important identified risk	Event-level medical review; tolerability trend review; device human-factors input
Serious and opportunistic infections (including tuberculosis and hepatitis B reactivation)	TL1A antagonism dampens TH1/TH17 immunity; additive with corticosteroid/immunomodulator co-medication typical of this population	Important potential risk	Targeted review of all serious infections; pre-treatment screening data (tuberculosis, hepatitis B/C); specific follow-up questionnaire
Malignancy, with a pre-specified focus on epithelial/colorectal neoplasia	Chronic immunomodulation (class consideration) plus IL-22R agonism, which drives epithelial proliferation/regeneration, in a UC population at elevated background colorectal-cancer risk	Important potential risk	Long-latency vigilance; observed-versus-expected and registry-based analysis; specific follow-up questionnaire; continuation of standard UC colorectal surveillance
Immunogenicity-related events (hypersensitivity, administration/systemic reactions, loss of efficacy attributable to ADA)	Humanised bispecific IgG1 can elicit binding and neutralising ADA affecting exposure, efficacy and, less commonly, safety	Important potential risk	Integrated review of ADA (Section 10) with PK, efficacy and safety; hypersensitivity follow-up questionnaire
Hepatic laboratory changes	IL-22R is expressed on hepatocytes as well as intestinal epithelium; mechanism-informed monitoring rather than an established concern	Monitored under long-term safety (missing information)	Review of liver-function trends in aggregate safety data
Events in pregnancy/lactation and long-term safety	Placental IgG (FcRn) transfer; controlled exposure limited to 12-week induction	Missing information	Enhanced pregnancy-outcome surveillance and long-term study data feeding future signal review

10. Immunogenicity signal management

Immunogenicity is integral to signal management for TILA-278 and is handled with a validated, tiered assay strategy: a screening tier, a confirmatory tier, titre determination, and a neutralising-antibody (NAb) tier, supported by characterisation of ADA impact on pharmacokinetics, efficacy and safety. Because the molecule exhibits target-mediated (TMDD) pharmacokinetics, ADA-related changes in exposure can manifest as attenuated exposure and secondary loss of clinical effect; signal management therefore evaluates ADA status jointly with PK and efficacy rather than in isolation. Over the 12-week induction period the observed ADA incidence was low and without a clear impact on remission rates or safety; however, durable exposure and repeat-dosing data are required to characterise ADA incidence, titre, persistence and neutralising potential, and immunogenicity is accordingly carried as an important potential risk. Immunogenicity signals — including any temporal association of ADA with hypersensitivity, injection-site or systemic administration reactions, or with loss of response — are prioritised and assessed under Sections 6–8, and are reported cumulatively in the DSUR and in the dedicated immunogenicity summary.

11. Documentation, tracking and record-keeping

All signal management activity is recorded in a controlled, auditable signal tracking system that captures, for each signal: the source and date of detection; the detection method (qualitative review, statistical flag, literature, regulatory source); the validation outcome and rationale; the prioritisation category; the assessment and its conclusion; the recommendation and any resulting action; responsible individuals; and key dates and status. The tracking system provides the evidence trail for periodic reporting and for regulatory inspection, and is the reconciliation source for the signal and risk sections of the DSUR, the PBRER/PSUR and the RMP. Retention and quality-control of records follow the sponsor's pharmacovigilance system (Pharmacovigilance System Master File, referenced separately).

12. Timelines, periodicity and communication

Signal detection is continuous. Aggregate qualitative review is performed on a defined periodicity (at minimum monthly during active clinical conduct, and at each DSUR data lock point); post-authorisation, spontaneous and EVDAS/FAERS data are screened at a frequency proportionate to the accumulating exposure and reporting volume. Validation of a detected signal is targeted for completion within 30 calendar days of detection, with prioritised or emerging issues handled sooner. An emerging safety issue that may require immediate action is escalated to the QPPV/Signal Review Team and notified to the relevant competent authorities within 3 working days, independent of the routine periodic cycle. Confirmed signals and their consequences are communicated to competent authorities and, in the EU, to the PRAC as required, and are reflected in the RSI/product information, the RMP and the next periodic safety document. Urgent safety restrictions, direct healthcare-professional communications and other proactive measures are deployed where a signal warrants immediate risk minimisation.

13. Interfaces with other pharmacovigilance and regulatory documents

The SMP is the connective process linking the safety data sources to the sponsor's benefit-risk governance. Its outputs feed, and are reconciled with:

• the Risk Management Plan (M1-RMP) — safety specification, pharmacovigilance plan and risk-minimisation measures;
• the Development Safety Update Report (DSUR-001, ICH E2F) — cumulative and interval signal and risk evaluation during development;
• the Periodic Benefit-Risk Evaluation Report (PSUR-001 / PBRER, ICH E2C(R2)) — integrated benefit-risk evaluation once authorised;
• the Reference Safety Information (Investigator's Brochure during development; Company Core Data Sheet / approved product information after authorisation) — expectedness and labelling;
• the immunogenicity summary and clinical pharmacology reporting — ADA, TMDD PK and exposure–response context.

Benefit is weighed against the characterised and emerging risks in this process. In the pivotal induction study TILA278-201, TILA-278 produced a clinically meaningful, dose-ordered effect — clinical remission (modified Mayo score ≤ 2 with no individual subscore > 1) at Week 12 in 37.3% (106/284) of High-dose and 16.2% (46/283) of Low-dose subjects versus 0.7% (2/273) on placebo; LS-mean change from baseline in modified Mayo score −3.36 (High), −2.76 (Low) and −1.00 (placebo), differences versus placebo −2.36 and −1.77; and endoscopic improvement in 48.9%, 27.9% and 6.2%, respectively — against a favourable short-term safety profile in which injection-site reactions were the principal drug-attributable finding and no dose-dependent safety signal was observed. This SMP ensures that, as exposure accrues, any change to that balance is detected early, evaluated rigorously and acted upon. GVP Module IX.