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Module 1 (KR) — Risk Management Plan (TILA-278)

Document ID: M1-KR-RMP
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): MFDS / ICH E2E

Korea (MFDS) Risk Management Plan — TILA-278

Korea-specific RMP for TILA-278: safety specification, pharmacovigilance plan, and risk-minimisation aligned to MFDS expectations and the EU RMP.

This Risk Management Plan (위해성 관리 계획, RMP) has been prepared in accordance with the Ministry of Food and Drug Safety (MFDS) requirements under the Regulation on Safety of Drugs, Etc. and the MFDS guideline on the preparation of drug risk management plans, and is consistent with the principles of ICH E2E. It is aligned in structure and content with the EU RMP (Document M1-RMP) and the U.S. risk-management assessment, and is submitted in support of the biological product licence application for TILA-278 (tilarudimab), a recombinant humanised IgG1 bispecific monoclonal antibody of Virtual Biopharma Inc. The safety profile described here is characterised principally from the pivotal Phase 2b induction study TILA278-201; efficacy is summarised only to frame the benefit against which the risks are weighed, with the full benefit-risk assessment presented in Module 2.5. As a new biological product, TILA-278 is expected to be subject to a re-examination period (재심사), and this RMP is intended to operate together with the associated post-marketing surveillance obligations described in this document.

1. Product overview (제품 개요)

Table 1 — Product overview

Item	Description
Active substance (INN)	Tilarudimab (development code TILA-278)
Product class / modality	Recombinant humanised IgG1 bispecific monoclonal antibody, produced by Chinese hamster ovary (CHO) cell culture and purified by a Protein A capture and polishing chromatography downstream process
Applicant / licence holder	Virtual Biopharma Inc.
ATC code	L04AC (selective immunosuppressants; interleukin/TNF-superfamily modulators)
Pharmaceutical form and route	Solution for injection in a single-use pre-filled syringe and pre-filled pen (autoinjector); subcutaneous (SC) administration
Strengths	150 mg and 300 mg per device
Mechanism of action	Dual, complementary pharmacology delivered by a single bispecific molecule. One arm is an antagonist of TL1A (TNFSF15), dampening TH1/TH17-driven inflammation and intestinal fibrosis; the second arm is an agonist of the IL-22 receptor, driving intestinal epithelial regeneration and mucosal-barrier repair. The net effect combines anti-inflammatory/anti-fibrotic activity with active mucosal healing.
Proposed indication	Treatment of adults with moderately-to-severely active ulcerative colitis (UC) who have had an inadequate response, loss of response, or intolerance to conventional therapy or a biologic agent
Posology (proposed)	SC induction dosing at Weeks 0, 2, 4, 8 and 12, followed by maintenance dosing; self-administration after appropriate training
Pharmacokinetics	Target-mediated drug disposition (TMDD), with non-linear clearance at lower concentrations reflecting saturable binding to TL1A and IL-22R; elimination otherwise by proteolytic catabolism to peptides and amino acids
Authorisation status	Under initial evaluation; not yet authorised in any region

The clinical rationale is supported by the pivotal Phase 2b induction study TILA278-201 in 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: clinical remission 37.3% (106/284) for High-dose, 16.2% (46/283) for Low-dose and 0.7% (2/273) for placebo (full analysis set, FAS). The LS-mean change from baseline in modified Mayo score was −3.36 (High), −2.76 (Low) and −1.00 (placebo), with differences versus placebo of −2.36 (95% CI −2.49, −2.23) and −1.77 (95% CI −1.90, −1.64), both p < 0.0001; endoscopic improvement was observed in 48.9%, 27.9% and 6.2% of subjects, respectively.

2. Safety specification (안전성 중점 검토 항목)

2.1 Epidemiology of the indication and target population

Ulcerative colitis is a chronic, relapsing-remitting inflammatory bowel disease. In the Republic of Korea, both incidence and prevalence have risen markedly over recent decades in parallel with westernisation of diet and lifestyle, although the absolute burden remains lower than in Northern and Western Europe; nationwide claims-based estimates place the prevalence in the order of tens per 100,000 with a continuing upward trend, onset predominantly in early-to-middle adulthood, and an approximately equal sex distribution. The target population for TILA-278 is the moderate-to-severe subset who have failed conventional therapy (5-aminosalicylates, corticosteroids, thiopurines) and/or a biologic or targeted synthetic agent, characterised by extensive/left-sided colitis, higher corticosteroid exposure, greater cumulative immunosuppressant burden, and elevated rates of colectomy and hospitalisation.

Important comorbidities relevant to the interpretation of on-treatment events include 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. Two background exposures carry particular weight in the Korean setting: the population-level burden of tuberculosis remains among the highest in the OECD, and the historical intermediate endemicity of hepatitis B virus (HBV) infection is relevant to the risk of reactivation under immunomodulatory therapy. 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.

2.2 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 designed in accordance with ICH S6(R1):

• Primary pharmacology. Anti-TL1A neutralisation and IL-22R agonism were confirmed in vitro; in vivo pharmacology in disease models using a species-appropriate surrogate/knock-in supported the combined anti-inflammatory/anti-fibrotic and mucosal-healing hypothesis.
• Relevant species and repeat-dose toxicology. The cynomolgus monkey was the sole pharmacologically relevant toxicology species. Repeat-dose toxicity was evaluated 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 with no target-organ toxicity of concern.
• Tissue cross-reactivity on human and cynomolgus tissue panels showed binding consistent with the known target distribution, with no unexpected off-tissue binding.
• Safety pharmacology endpoints (cardiovascular, respiratory, CNS), assessed within the repeat-dose programme, revealed no adverse effects. Consistent with ICH S6(R1)/S7B and E14, dedicated hERG and thorough-QT studies are 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 proliferative concern arising from chronic immunomodulation, and specifically from IL-22R agonism on epithelial tissue, is addressed as a clinical potential risk (Section 2.5) 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.
• Quality-related safety. Viral safety and adventitious-agent control of the CHO-derived substance follow ICH Q5A(R2); stability and specifications follow ICH Q5C and Q6B, respectively. These are addressed in Modules 2.3/3 and do not give rise to a stand-alone clinical safety concern.

No non-clinical finding translates into a stand-alone safety concern beyond those 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.

2.3 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 visits at Weeks 0, 2, 4, 8 and 12). The safety analysis set comprised all randomised subjects who received at least one dose.

Table 2 — Extent of exposure (TILA278-201, safety set)

Exposure category	TILA-278 High	TILA-278 Low	Placebo	Total active
Subjects randomised	299	300	301	599
Subjects exposed (≥ 1 dose)	299	300	301	599
Planned treatment duration	12 weeks (induction)	12 weeks (induction)	12 weeks (induction)	—
Approx. person-time	~68.7 patient-years	~68.9 patient-years	~69.1 patient-years	~137.6 patient-years

Table 3 — Exposure by demographic category (active arms combined)

Category	Proportion of exposed subjects
Age < 65 years	~92%
Age ≥ 65 years	~8%
Female / Male	~44% / ~56%
Prior biologic exposure (stratification factor)	~50%

Exposure to date is limited to a 12-week induction period in an adult, predominantly < 65-year population, and experience in Korean/East-Asian subjects within this global study is limited. These limitations directly inform the long-term safety and special-population items in the missing information (Section 2.6).

2.4 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 a separate paediatric plan. Not carried as a stand-alone safety concern in this RMP.
• Elderly (≥ 65 years) — limited numbers enrolled; data insufficient to detect differences; discussed under long-term safety.
• Korean population — limited exposure within the global study; addressed as Korea-specific missing information and to be characterised through post-marketing surveillance (Section 5).
• 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/precautions.

2.5 Identified and potential risks

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 4.

Table 4 — Overview of treatment-emergent adverse events (TILA278-201, safety set)

Parameter, n (%)	TILA-278 High (N = 299)	TILA-278 Low (N = 300)	Placebo (N = 301)
≥ 1 TEAE	109 (36.5)	131 (43.7)	130 (43.2)
Serious adverse events	3 (1.0)	0	4 (1.3)
Deaths (all assessed as unrelated to study drug)	2 (0.7)	0	1 (0.3)
Discontinued study treatment (all causes)	17 (5.7)	17 (5.7)	29 (9.6)

TEAE frequency was similar across the active and placebo arms without a 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 (important identified risk). Injection-site reactions were the principal drug-attributable finding, 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.

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 — considerations of heightened relevance in Korea given the background tuberculosis burden and historical HBV endemicity. No excess of serious infection was observed over the 12-week induction period, but the short exposure and modest sample size preclude exclusion of a longer-term, class-consistent risk. The risk is preventable in part through pre-treatment screening (tuberculosis by interferon-γ release assay and/or chest radiograph; HBsAg and anti-HBc for hepatitis B; hepatitis 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 over 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.

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

2.6 Summary of the safety concerns

Table 5 — Summary of safety concerns

Category	Safety concern(s)
Important identified risks	Injection-site reactions
Important potential risks	Serious and opportunistic infections (including tuberculosis and hepatitis B reactivation); Malignancy (including epithelial/colorectal neoplasia); Immunogenicity with potential impact on efficacy or safety
Missing information	Long-term safety (beyond 12-week induction exposure); Use in pregnancy and breast-feeding; Limited experience in the Korean population

3. Pharmacovigilance plan (의약품 감시 계획)

3.1 Routine pharmacovigilance activities

Routine pharmacovigilance is conducted in accordance with the sponsor's pharmacovigilance system and MFDS reporting obligations, and comprises:

• Continuous collection, medical review and expedited/periodic reporting of adverse reactions, including reporting to MFDS and the Korea Institute of Drug Safety & Risk Management (KIDS) through the Korea Adverse Event Reporting System (KAERS / 의약품안전나라).
• Ongoing signal detection and evaluation, with periodic benefit-risk reporting in the periodic safety update report (PSUR/PBRER) submitted to MFDS.
• Targeted follow-up questionnaires (specific adverse-reaction follow-up forms) for serious infections (including tuberculosis and hepatitis B reactivation), malignancies, events suggestive of hypersensitivity/immunogenicity, and reports of exposure during pregnancy and breast-feeding.

3.2 Additional pharmacovigilance activities

Table 6 — Additional pharmacovigilance activities

Study / activity (status)	Safety concern(s) addressed	Objectives	Milestones (planned)
TILA278-301 — long-term controlled maintenance and open-label extension study (required activity)	Long-term safety; serious infections; malignancy; immunogenicity	Characterise safety over ≥ 52 weeks of maintenance dosing, including serious/opportunistic infection, malignancy, ADA incidence/persistence/neutralising potential and durability of effect	Protocol finalised at approval; annual interim safety reports with each PSUR; final clinical study report
Post-marketing surveillance (use-results survey, 사용성적조사) — prospective observational cohort in Korean patients (required activity linked to re-examination)	Serious and opportunistic infections; Malignancy; Limited experience in the Korean population	Characterise the safety profile in routine Korean clinical practice, with attention to tuberculosis/hepatitis B reactivation and unexpected adverse reactions	Protocol at approval; interim reports through the re-examination period; final re-examination submission
Registry-based safety study — participation in an IBD registry/cohort (required activity)	Serious and opportunistic infections; Malignancy	Estimate incidence of serious infection and of malignancy (pre-specified focus on colorectal/epithelial neoplasia) versus a UC comparator cohort	Interim analyses during the surveillance period; final report at completion
Pregnancy outcomes surveillance — enhanced pregnancy follow-up / participation in an IBD-pregnancy registry (required activity)	Use in pregnancy and breast-feeding	Collect and evaluate maternal, foetal and infant outcomes following in-utero/lactational exposure	Enrolment from approval; annual reporting with each PSUR
Immunogenicity characterisation — ongoing tiered ADA assessment embedded in TILA278-301 and future studies	Immunogenicity	Define ADA incidence, titre, persistence and neutralising capacity, and impact on PK/efficacy/safety	Reported with each periodic safety update

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

4. Risk minimisation measures (위해성 완화 조치)

4.1 Routine risk minimisation measures

Routine risk minimisation is achieved through the MFDS-approved label (사용상의 주의사항), the patient information, the container/carton labelling, the device/pack design, and the legal status of a prescription-only medicine administered under the supervision of a physician experienced in the management of UC.

Table 7 — Routine risk minimisation measures by safety concern

Safety concern	Routine risk minimisation measures
Injection-site reactions	Label description of frequency/nature; patient guidance and training on injection technique and site rotation; device design; prescription-only status
Serious and opportunistic infections	Contraindication in active serious infection; precautions on infection risk, mandatory screening for tuberculosis and hepatitis B before initiation, guidance on interruption during serious infection, and vaccination review; prescriber restriction to specialists
Malignancy	Precaution on immunomodulation and theoretical neoplasia risk, including continuation of standard UC colorectal-cancer surveillance; prescriber restriction
Immunogenicity	Precaution on hypersensitivity/immunogenicity, ADA information, and guidance on management of hypersensitivity reactions; prescription-only status
Long-term safety (missing information)	Label wording reflecting the limited duration of controlled exposure; routine update as data mature
Use in pregnancy and breast-feeding (missing information)	Precaution addressing use during pregnancy and lactation, including placental IgG transfer and implications for infant live-vaccination timing; patient guidance
Limited experience in the Korean population (missing information)	Post-marketing characterisation in Korean patients under the re-examination programme; label update as data accrue

4.2 Additional risk minimisation measures

A Patient Alert Card (환자안전카드) 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 that may increase susceptibility to infection; list symptoms/signs (including those of tuberculosis and hepatitis B reactivation) 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. A concise healthcare-professional guide reinforcing pre-treatment tuberculosis and hepatitis B screening and management is proposed alongside the card. The effectiveness of these measures will be evaluated as part of routine pharmacovigilance and periodic RMP updates.

Table 8 — Summary of risk minimisation measures

Safety concern	Routine RMM	Additional RMM
Injection-site reactions	Yes	None
Serious and opportunistic infections	Yes	Patient Alert Card; HCP guide
Malignancy	Yes	None
Immunogenicity	Yes	None
Long-term safety	Yes	None
Use in pregnancy and breast-feeding	Yes	None
Limited experience in the Korean population	Yes	None

5. Post-marketing surveillance and re-examination (시판 후 조사 및 재심사)

As a new biological product, TILA-278 is expected to be designated for re-examination (재심사) by MFDS. During the re-examination period the sponsor will conduct a post-marketing use-results survey (사용성적조사) in Korean patients to characterise the safety profile in routine clinical practice, together with a specified-use-results survey (특별조사) directed at the important potential risks — in particular serious and opportunistic infections (with attention to tuberculosis and hepatitis B reactivation) and malignancy. The target sample size, survey design and reporting schedule will be finalised in agreement with MFDS at the time of approval, consistent with the standard re-examination requirement for a new drug. Data from these surveys, together with the outputs of the additional pharmacovigilance activities in Section 3.2 and periodic safety reporting, will form the basis of the re-examination submission and will be used to update the safety specification and, where warranted, the approved label and the risk minimisation measures in this plan.

6. Summary of the risk management plan (요약)

Overview of disease epidemiology. Ulcerative colitis is a chronic relapsing-remitting inflammatory bowel disease with rising incidence and prevalence in Korea, peak onset in early-to-middle 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) and endoscopic improvement in 48.9%, 27.9% and 6.2% of subjects, respectively. The dual mechanism — TL1A antagonism plus IL-22R agonism — combines anti-inflammatory/anti-fibrotic activity with active mucosal healing.

Unknowns. Controlled experience is currently limited to a 12-week induction period in adults, with limited Korean exposure; 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 (including tuberculosis and hepatitis B reactivation); malignancy (including epithelial/colorectal neoplasia); immunogenicity. Missing information: long-term safety; use in pregnancy and breast-feeding; limited experience in the Korean population.

Summary of risk minimisation and pharmacovigilance. All concerns are managed by routine risk minimisation (approved label, patient information, labelling, specialist prescription), with a Patient Alert Card and a healthcare-professional guide as additional measures for serious infection. Beyond routine pharmacovigilance (including targeted follow-up questionnaires and KAERS reporting), the sponsor will conduct a long-term maintenance/extension study (TILA278-301), a post-marketing use-results survey and registry-based safety study focused on serious infection and malignancy, enhanced pregnancy-outcome surveillance, and ongoing immunogenicity characterisation, operating together with the re-examination programme.

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 and surveillance activities in this plan.

7. Annexes (부록)

• Annex 1 — Product and marketing-authorisation information for MFDS reporting.
• Annex 2 — Tabulated summary of planned, ongoing and completed pharmacovigilance and post-marketing surveillance programme.
• Annex 3 — Protocols for proposed, ongoing and completed studies in the pharmacovigilance plan (TILA278-301; use-results survey; registry-based safety study; pregnancy surveillance).
• Annex 4 — Specific adverse-drug-reaction follow-up forms.
• Annex 5 — Details of proposed additional risk minimisation measures (Patient Alert Card; healthcare-professional guide).
• Annex 6 — Other supporting data, including references.
• Annex 7 — Summary of changes to the risk management plan over time (this version: initial RMP, aligned to the data lock point of study TILA278-201).