Risk Management Plan (TILA-278)

Region-specific administrative document for the TILA-278 marketing application.

Change History

Part I: Product(s) Overview

This Risk Management Plan (RMP) has been prepared in accordance with EU Good Pharmacovigilance Practices (GVP) Module V (Rev 2) and the format of the revised EU RMP template, and is consistent with the principles of ICH E2E. It describes the safety profile of TILA-278 (Virtual Biopharma Inc.) as characterised in the pivotal induction study TILA278-201, sets out the sponsor's plan to further characterise and monitor the safety concerns, and specifies the measures proposed to minimise the identified and potential risks in clinical use.

Table I.1 — Product overview

The clinical rationale is supported by the pivotal Phase 2b induction study TILA278-201 (moderate-to-severe UC), in which the primary endpoint of clinical remission (modified Mayo score ≤ 2 with no individual subscore > 1) at Week 12 was met with a clear dose-ordered effect (LS-mean change from baseline in modified Mayo score −3.36 [High], −2.76 [Low] and −1.00 [placebo]; difference versus placebo −2.36 [95% CI −2.49, −2.23] for High and −1.77 [95% CI −1.90, −1.64] for Low, both p < 0.0001; clinical remission 37.3% [106/284], 16.2% [46/283] and 0.7% [2/273], respectively; full analysis set [FAS]). Efficacy data are summarised here only to frame the benefit against which the risks in this RMP are weighed; the full benefit-risk assessment is presented in Module 2.5.

Part II: Safety Specification

Module SI — Epidemiology of the indication and target population

Indication. Moderately-to-severely active ulcerative colitis in adults.

Incidence and prevalence. UC is a chronic, relapsing-remitting inflammatory bowel disease. In the EU, the reported prevalence is of the order of 250–500 per 100,000 and the annual incidence approximately 10–20 per 100,000, with the highest rates in Northern and Western Europe. Onset peaks between 15 and 35 years of age, with a smaller second peak in the sixth decade; the sex distribution is approximately equal.

Demographics and disease course. The target population for TILA-278 is the moderate-to-severe subset who have failed conventional therapy (5-aminosalicylates, corticosteroids, thiopurines) and/or biologic or targeted therapy. This population is characterised by extensive/left-sided colitis, higher corticosteroid exposure, greater cumulative immunosuppressant burden, and elevated rates of colectomy and hospitalisation.

Important comorbidities. Iron-deficiency and inflammatory anaemia, extra-intestinal manifestations (arthralgia/spondyloarthropathy, uveitis, primary sclerosing cholangitis), venous thromboembolism, and an elevated long-term risk of colorectal dysplasia and carcinoma related to chronic mucosal inflammation and disease duration. These background risks are relevant to the interpretation of on-treatment events; anaemia, arthralgia and malignancy in particular are also expected background events in this population.

Important co-medication. Concomitant corticosteroids, immunomodulators (azathioprine/6-mercaptopurine, methotrexate) and other biologics/targeted synthetic agents are common and contribute to a shared background of infection and malignancy risk that must be considered when attributing on-treatment events to TILA-278.

Module SII — Non-clinical part of the safety specification

Because TL1A and the IL-22 receptor are engaged by TILA-278 with human target specificity, conventional rodents are not pharmacologically relevant. The non-clinical package was therefore designed in accordance with ICH S6(R1):

• Primary pharmacology / disease models. Anti-TL1A neutralisation and IL-22R agonism were confirmed in vitro; in vivo pharmacology was investigated in disease models using a species-appropriate surrogate/knock-in, supporting the combined anti-inflammatory and mucosal-healing hypothesis.
• Repeat-dose toxicology. Conducted in the cynomolgus monkey by the intended SC route (up to 26 weeks). The no-observed-adverse-effect level (NOAEL) was the highest dose tested, providing an exposure margin of approximately 10× over the anticipated clinical exposure. Findings were limited to exaggerated pharmacology; no target-organ toxicity of concern was identified.
• Tissue cross-reactivity studies on human and cynomolgus tissue panels showed binding consistent with the known distribution of the targets, with no unexpected off-tissue binding.
• Safety pharmacology endpoints (cardiovascular, respiratory, CNS), assessed as part of the repeat-dose programme, revealed no adverse effects. Consistent with ICH S7B/E14, a dedicated thorough-QT study is not warranted for a monoclonal antibody with no expectation of direct ion-channel interaction.
• Genotoxicity and carcinogenicity. Standard genotoxicity and rodent carcinogenicity studies are not applicable to a monoclonal antibody per ICH S6(R1). The theoretical carcinogenic/proliferative concern arising from chronic immunomodulation, and specifically from IL-22R agonism on epithelial tissue, is addressed as a clinical potential risk (see Module SVII) rather than through rodent bioassays.
• Reproductive and developmental toxicity. As an IgG1 that crosses the placenta (predominantly in the second and third trimesters via FcRn), enhanced pre-/post-natal development assessment in the non-human primate is the relevant paradigm; definitive data are not yet available and use in pregnancy is carried as missing information.

Conclusion on non-clinical concerns. No non-clinical finding translates into a stand-alone safety concern beyond those already captured clinically. The mechanistic signals (immunosuppression from TL1A antagonism; epithelial proliferation from IL-22R agonism) are reflected in the potential risks of serious infection and malignancy.

Module SIII — Clinical trial exposure

Exposure derives from the pivotal Phase 2b induction study TILA278-201 (randomised, double-blind, placebo-controlled, parallel-group; 1700 screened, 900 randomised 1:1:1 to TILA-278 High / TILA-278 Low / Placebo; stratified by baseline modified Mayo severity and prior biologic exposure; scheduled study visits at Weeks 0, 2, 4, 8 and 12). The safety analysis set comprised all randomised subjects who received at least one dose.

Table SIII.1 — Extent of exposure (TILA278-201, safety set)

Table SIII.2 — Exposure by demographic category (active arms combined)

Exposure to date is limited to a 12-week induction period and to an adult, predominantly < 65-year population; this directly informs the long-term safety and special-population items in the missing information (Module SVIII).

Module SIV — Populations not studied in clinical trials

The following populations were not, or were only minimally, studied in TILA278-201 and are addressed as exclusions and/or missing information:

• Pregnant and breast-feeding women — excluded; no clinical data (missing information).
• Paediatric population (< 18 years) — not studied; development addressed through an agreed Paediatric Investigation Plan (PIP) with deferral. Not carried as a separate safety concern in this RMP.
• Elderly (≥ 65 years) — limited numbers enrolled; data insufficient to detect differences, discussed under long-term safety.
• Renal or hepatic impairment — dedicated studies not required for a monoclonal antibody eliminated by proteolytic catabolism/target-mediated disposition rather than renal or hepatic routes; no specific dose adjustment is anticipated.
• Patients with active or chronic serious infection, latent tuberculosis without adequate treatment, or recent malignancy — excluded by protocol; these exclusions are reflected in the proposed contraindications/warnings.

Module SV — Post-authorisation experience

TILA-278 is not authorised in any region. There is no post-authorisation exposure and no cumulative post-marketing safety experience at the data lock point of this RMP.

Module SVI — Additional EU requirements for the safety specification

• Potential for misuse for illegal purposes: negligible. TILA-278 is a parenteral biologic with no abuse potential and no recreational value; specialist prescription and cold-chain distribution further limit any risk.
• Potential for medication errors: device-related administration errors and dosing errors are addressed through device human-factors design, clear SmPC/PL instructions and patient training; routine pharmacovigilance is considered sufficient.

Module SVII — Identified and potential risks

Overview of the clinical safety database. The safety characterisation of TILA-278 is based on the 12-week induction study TILA278-201. An overview of treatment-emergent adverse events (TEAEs) is presented in Table SVII.1.

Table SVII.1 — Overview of treatment-emergent adverse events (TILA278-201, safety set)

TEAE frequency was similar across the active and placebo arms and showed no dose-dependent gradient. Serious adverse events and deaths were infrequent and not more common on active treatment; all deaths were assessed as unrelated to study drug. Treatment discontinuation was highest on placebo and was driven predominantly by lack of efficacy. The most frequently reported TEAEs were nasopharyngitis, headache, worsening UC (more frequent on placebo), anaemia, arthralgia, upper respiratory tract infection, injection-site reactions (more frequent on active SC treatment) and nausea. Injection-site reactions were the principal drug-attributable finding.

SVII.1 Newly identified/important risks and the evidence

Injection-site reactions (important identified risk). Injection-site reactions were the principal drug-attributable finding in TILA278-201, reported more frequently in the active SC arms than on placebo (approximately 8–12% versus approximately 3%) and without a dose-dependent gradient between the High and Low arms. Events were predominantly mild-to-moderate, transient and local (erythema, pain, pruritus, swelling), and did not lead to a meaningful excess of treatment discontinuation. This is a well-understood, largely preventable and manageable local effect intrinsic to SC biologic administration and is therefore classified as an important identified risk.

Serious and opportunistic infections (important potential risk). TL1A antagonism dampens TH1/TH17 immunity; in combination with the immunomodulator/biologic co-medication typical of this population, this creates a mechanistically plausible potential for serious bacterial, viral, fungal and opportunistic infections, including reactivation of latent tuberculosis and hepatitis B. No excess of serious infection was observed over the 12-week induction period (serious adverse events 3/0/4, with no infection-driven imbalance versus placebo), but the short exposure and modest sample size preclude exclusion of a longer-term, class-consistent risk. Risk factors include concomitant corticosteroids/immunomodulators, advanced age, comorbidity and prior latent infection. The risk is preventable in part through pre-treatment screening (tuberculosis, hepatitis B/C), vaccination review, and patient/physician awareness.

Malignancy (important potential risk). Two strands support this potential risk. First, chronic immunomodulation is a recognised class consideration for agents used in immune-mediated inflammatory disease. Second, and specific to this molecule, IL-22R agonism promotes epithelial proliferation and regeneration — the very property that drives mucosal healing — and IL-22 has been implicated experimentally in epithelial and colorectal tumour biology; sustained receptor agonism therefore warrants specific long-term vigilance for epithelial/colorectal neoplasia in a UC population already at elevated background colorectal-cancer risk. No malignancy signal was identified in the 12-week induction study, but latency and exposure duration make this an inherently long-term question that cannot be resolved by induction data.

Immunogenicity (important potential risk). As a humanised bispecific IgG1, TILA-278 can elicit anti-drug antibodies (ADA), including neutralising antibodies, with potential to reduce exposure and efficacy or, less commonly, to contribute to hypersensitivity or injection-site/systemic administration reactions. Immunogenicity is assessed with a validated tiered assay (screening, confirmatory, titre and neutralising-antibody tiers) with characterisation of the impact of ADA on PK, efficacy and safety. Observed ADA incidence over induction was low and without a clear clinical impact on remission rates or safety; because durable exposure and repeat-dosing data are needed to characterise incidence, persistence and neutralising potential, immunogenicity is carried as an important potential risk.

SVII.2 Risks considered but not included as safety concerns

• Common, non-serious TEAEs (nasopharyngitis, headache, upper respiratory tract infection, nausea, arthralgia) were reported at rates consistent with the background disease/population and were not dose-related; these are adequately handled in SmPC section 4.8 and do not require RMP-level management.
• Anaemia and worsening UC were more frequent on placebo than on active treatment (consistent with disease activity and lack of efficacy) and are not treated as risks attributable to TILA-278.
• QT prolongation / cardiac ion-channel effects — not expected for a monoclonal antibody (ICH E14/S7B waiver rationale); not a safety concern.

Module SVIII — Summary of the safety concerns

Table SVIII.1 — Summary of safety concerns

Part III: Pharmacovigilance Plan

III.1 Routine pharmacovigilance activities

Routine pharmacovigilance beyond adverse-reaction collection and signal management is proposed for the safety concerns, comprising:

• Continuous collection, medical review and expedited/periodic reporting of adverse reactions in line with the sponsor's pharmacovigilance system (PSMF referenced separately).
• Ongoing signal detection and evaluation, with periodic benefit-risk evaluation reported in the PSUR/PBRER.
• Targeted follow-up questionnaires (specific adverse-reaction follow-up forms) for: serious infections (including tuberculosis/hepatitis B reactivation), malignancies, events suggestive of hypersensitivity/immunogenicity, and reports of exposure during pregnancy and breast-feeding.

III.2 Additional pharmacovigilance activities

Table III.1 — Additional pharmacovigilance activities

No additional pharmacovigilance activity beyond routine is proposed specifically for injection-site reactions, which are well characterised and adequately monitored by routine methods.

Part IV: Plans for Post-Authorisation Efficacy Studies

The long-term maintenance study TILA278-301 will also generate maintenance-of-remission and durability efficacy data. Whether a formal post-authorisation efficacy study (PAES) is imposed is subject to agreement with the competent authority at the time of the opinion; no PAES is otherwise proposed at this time.

Part V: Risk Minimisation Measures

V.1 Routine risk minimisation measures

Routine risk minimisation for TILA-278 is achieved through the SmPC, the package leaflet (PL), the labelling, the device/pack design, and the legal status of a medicine restricted to prescription and administration under the supervision of a physician experienced in the management of UC.

Table V.1 — Description of routine risk minimisation measures by safety concern

V.2 Additional risk minimisation measures

A Patient Alert Card is proposed as an additional risk minimisation measure to support early recognition and management of serious infection. The card will:

• inform patients that they are receiving an immunomodulatory biologic and that this may increase susceptibility to infection;
• list symptoms/signs that should prompt urgent medical attention;
• instruct patients to carry the card and present it to any treating healthcare professional (including in emergency and peri-operative settings); and
• include prescriber contact details.

The effectiveness of the Patient Alert Card will be evaluated as part of routine pharmacovigilance and periodic RMP updates. No additional risk minimisation measures beyond routine are proposed for injection-site reactions, malignancy, immunogenicity or the missing-information items, for which routine measures and the planned pharmacovigilance activities are considered proportionate and sufficient.

Table V.2 — Summary of risk minimisation measures

Part VI: Summary of the Risk Management Plan

Overview of disease epidemiology. Ulcerative colitis is a chronic relapsing-remitting inflammatory bowel disease affecting a substantial adult population in the EU, with peak onset in early adulthood and important comorbidity including anaemia, thromboembolism and an elevated long-term risk of colorectal cancer.

Summary of benefits. In the pivotal Phase 2b induction study TILA278-201, TILA-278 produced a clinically meaningful, dose-ordered improvement in moderate-to-severe UC: clinical remission 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, with LS-mean changes from baseline in modified Mayo score of −3.36 and −2.76 versus −1.00 on placebo (differences versus placebo −2.36 [95% CI −2.49, −2.23] and −1.77 [95% CI −1.90, −1.64], both p < 0.0001). The dual mechanism — TL1A antagonism plus IL-22R agonism — is designed to combine anti-inflammatory activity with active mucosal healing.

Unknowns. Controlled experience is currently limited to a 12-week induction period in adults; long-term safety, use in pregnancy and breast-feeding, and the long-latency question of malignancy remain to be characterised.

Summary of safety concerns. Important identified risk: injection-site reactions. Important potential risks: serious and opportunistic infections; malignancy (including epithelial/colorectal neoplasia); immunogenicity. Missing information: long-term safety; use in pregnancy and breast-feeding.

Summary of risk minimisation and pharmacovigilance. All concerns are managed by routine risk minimisation (SmPC, PL, labelling, specialist prescription), with a Patient Alert Card as an additional measure for serious infection. Beyond routine pharmacovigilance (including targeted follow-up questionnaires), the sponsor will conduct a long-term maintenance/extension study (TILA278-301), a registry-based PASS focused on serious infection and malignancy, enhanced pregnancy-outcome surveillance, and ongoing immunogenicity characterisation.

Overall benefit-risk. On the basis of a clear, dose-ordered efficacy signal and 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, the benefit-risk balance of TILA-278 in moderate-to-severe UC is considered positive, subject to confirmation of long-term safety through the pharmacovigilance activities in this plan.

Part VII: Annexes

• Annex 1 — EudraVigilance / Extended EudraVigilance Medicinal Product Report Message (XEVMPD) information.
• Annex 2 — Tabulated summary of planned, ongoing and completed pharmacovigilance study programme.
• Annex 3 — Protocols for proposed, ongoing and completed studies in the pharmacovigilance plan (TILA278-301; PASS; pregnancy surveillance).
• Annex 4 — Specific adverse-drug-reaction follow-up forms.
• Annex 5 — Protocols for proposed and ongoing studies in Part IV (if applicable).
• Annex 6 — Details of proposed additional risk minimisation measures (Patient Alert Card).
• Annex 7 — Other supporting data, including references.
• Annex 8 — Summary of changes to the risk management plan over time (this version: initial RMP, aligned to the data lock point of study TILA278-201).