Module 1 — Pediatric Study Plan (PSP/PIP) (TILA-278)

Document ID: M1-PED
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): PREA/BPCA; EU 1901/2006

Pediatric Study Plan (PSP / PIP) — TILA-278

The initial pediatric study plan (US iPSP) and EU paediatric investigation plan for TILA-278 in Ulcerative Colitis (moderate-to-severe): the proposed pediatric development, age-appropriate formulation considerations, planned studies or a request for waiver/deferral with justification. PREA/BPCA; EU Paediatric Regulation 1901/2006.

1. Scope, product and regulatory basis

This plan addresses the paediatric development of TILA-278 (INN tilarudimab; Virtual Biopharma Inc.), a recombinant humanised IgG1 bispecific monoclonal antibody produced in Chinese hamster ovary (CHO) cell culture and administered subcutaneously (SC), for the treatment of moderately-to-severely active ulcerative colitis (UC). TILA-278 delivers a single-molecule dual pharmacology: 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 proposed adult presentation is a solution for injection in single-use pre-filled syringe and pre-filled pen (autoinjector) at 150 mg and 300 mg per device, with induction dosing at Weeks 0, 2, 4, 8 and 12 followed by maintenance dosing (ATC provisional L04AC).

The plan is submitted concurrently in two regulatory frameworks:

• United States — an initial Pediatric Study Plan (iPSP) under the Pediatric Research Equity Act (PREA, FDARA/21 CFR) and the Best Pharmaceuticals for Children Act (BPCA), submitted in advance of the marketing application (the Biologics License Application will be filed under 21 CFR Part 601). Under PREA, the required paediatric assessment applies to the indication under review (moderate-to-severe UC) and to the relevant paediatric subpopulations in which that condition occurs.
• European Union — a Paediatric Investigation Plan (PIP) under Regulation (EC) No 1901/2006, for agreement by the Paediatric Committee (PDCO), comprising the proposed paediatric measures (quality/pharmaceutical, non-clinical and clinical) together with the requested waiver(s) and deferral.

The scope of this plan is limited to the condition "ulcerative colitis". No paediatric development is proposed for indications outside UC.

2. The condition in the paediatric population

Occurrence. Ulcerative colitis occurs in the paediatric population. Approximately one in five to one in four patients with inflammatory bowel disease present before 18 years of age, and paediatric-onset UC incidence has been rising over recent decades. Adolescents (12 to < 18 years) account for the majority of paediatric UC; disease is progressively less common in younger children. Very-early-onset IBD (VEO-IBD, typically < 6 years, and most distinctly < 2 years) is a comparatively rare and biologically distinct entity, frequently reflecting monogenic immune-regulatory defects rather than the polygenic, immune-mediated UC seen in adolescents and adults.

Disease characteristics and unmet need. Paediatric UC is frequently more extensive (pancolitis) at diagnosis, more often steroid-dependent or steroid-refractory, and carries a substantial burden on growth, pubertal development, schooling and psychosocial function. The therapeutic armamentarium approved for paediatric UC remains narrower than for adults, and loss of response to available biologics is common. A mechanism combining anti-inflammatory/anti-fibrotic TL1A antagonism with reparative IL-22R agonism is of particular interest in a growing patient in whom durable mucosal healing, avoidance of chronic corticosteroid exposure and reduction of long-term fibrostenotic/colectomy risk are priorities.

Basis for extrapolation. The pathophysiology of adolescent and older-child UC is considered continuous with that of adult UC, including the genetic contribution of the TL1A/TNFSF15 axis and the mucosal biology of IL-22. This supports a partial extrapolation-of-efficacy approach from the adult data for the older paediatric subsets, with confirmation through paediatric pharmacokinetic (PK)/exposure matching and safety characterisation. Extrapolation is not considered appropriate for the < 2-year subset, in which the underlying disease biology (VEO-IBD) differs and the mechanism is unlikely to be relevant.

3. Supporting adult efficacy and safety framing extrapolation

The adult evidence anchoring the paediatric plan is the 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; full analysis set [FAS] 840 [284 / 283 / 273]). 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: 37.3% (106/284) High, 16.2% (46/283) Low and 0.7% (2/273) placebo. Supportive key secondary endpoints were consistent, with LS-mean change from baseline in modified Mayo score of −3.36 (High), −2.76 (Low) and −1.00 (placebo) — differences versus placebo of −2.36 and −1.77 — and endoscopic improvement in 48.9%, 27.9% and 6.2%, respectively. The dose-ordered exposure-response relationship established in adults defines the target systemic exposure (that produced by the effective High regimen) to which paediatric dosing will be matched, and provides the efficacy anchor from which adolescent efficacy is partially extrapolated.

4. Mechanistic and developmental considerations specific to paediatrics

Two mechanistic features require explicit paediatric consideration:

• TL1A antagonism produces targeted immunomodulation. In a developing immune system, the theoretical consequences of dampening TH1/TH17 immunity — susceptibility to serious and opportunistic infection, response to vaccination (including live vaccines), and interaction with the paediatric immunisation schedule — must be characterised and monitored. Growth and pubertal development, which are adversely affected by uncontrolled disease and by chronic corticosteroid exposure, are to be followed as part of paediatric safety.
• IL-22R agonism drives epithelial proliferation and regeneration — the property underlying mucosal healing. In a developing gastrointestinal epithelium this reparative signal is potentially beneficial, but sustained receptor agonism warrants specific long-term vigilance for epithelial proliferation/neoplasia, consistent with the potential risk carried in the Risk Management Plan for the adult population. This is addressed through long-term follow-up rather than through short-term studies.

As an IgG1, TILA-278 is subject to FcRn-mediated recycling and, in the context of a treated pregnancy, transplacental transfer predominantly in the second and third trimesters; this is relevant to the timing of live-vaccine administration in infants exposed in utero and is reflected in labelling and in pregnancy-outcome surveillance. Elimination is by proteolytic catabolism and target-mediated drug disposition (TMDD) rather than renal or hepatic routes, informing the PK/dosing strategy below.

5. Proposed paediatric development programme (clinical)

Development is structured by ICH E11 age subsets and is staged, older-to-younger, to allow accruing PK/safety data to inform dosing in each successively younger subset:

Table PED.1 — Proposed clinical development by age subset

Extrapolation, modelling and simulation. A quantitative extrapolation framework underpins the plan. A population-PK model incorporating TMDD and allometric (body-weight) scaling, developed from the adult programme and refined with paediatric data as they accrue, will project paediatric doses that reproduce the adult systemic exposure associated with efficacy. Dosing in paediatric subsets is therefore weight-based or weight-band rather than the adult fixed-dose regimen. Adolescent efficacy is partially extrapolated from the adult exposure-response relationship and confirmed through PK/exposure matching plus PD (biomarker and endoscopic) and safety; efficacy in younger subsets relies more heavily on model-informed exposure matching with supportive clinical endpoints. Exposure targets, sampling schemes (sparse/opportunistic where appropriate to minimise paediatric burden) and the pre-specified acceptance criteria for exposure matching will be detailed in the individual paediatric study protocols.

Endpoints and assessments. Paediatric studies will employ disease-activity instruments validated for paediatric UC (including centrally-read endoscopy and paediatric-appropriate composite indices), with growth and pubertal (Tanner-stage) monitoring, and the tiered immunogenicity assessment described below. Where feasible and ethical, PK/PD assessments will be embedded to limit the number of dedicated procedures.

6. Immunogenicity, pharmacokinetics and safety monitoring in paediatrics

Consistent with the adult programme, anti-drug antibodies (ADA) will be assessed with a validated tiered assay (screening, confirmatory, titre and neutralising-antibody tiers), and the impact of ADA on PK, exposure, efficacy and safety characterised in each paediatric subset — a paediatric immune system may differ in the incidence, persistence and neutralising potential of ADA, and this is a specific object of study. PK will be characterised in the context of TMDD, with body-weight-based dosing to achieve the adult target exposure. Safety monitoring gives explicit attention to: serious and opportunistic infection (including tuberculosis and hepatitis B screening and reactivation, and the paediatric vaccination schedule, with live-vaccine precautions); injection-site reactions and administration tolerability; growth and development; and long-term epithelial/neoplasia vigilance. Long-term safety and durability will be captured through an extension and through the paediatric component of the pharmacovigilance activities described in the Risk Management Plan.

7. Non-clinical plan for paediatrics

The non-clinical strategy follows ICH S6(R1) for biotechnology-derived products and ICH S11 for the support of paediatric development, integrated with the existing adult package. The cynomolgus monkey is the sole pharmacologically relevant species (human target specificity precludes rodents), and the intended SC route is used.

• Juvenile-animal toxicity. The need for a dedicated juvenile-animal toxicity study is evaluated on a weight-of-evidence basis per ICH S11. The adult non-clinical package (repeat-dose toxicology in cynomolgus, tissue cross-reactivity and safety pharmacology within the repeat-dose study) and the enhanced pre-/post-natal development (ePPND) assessment in the non-human primate together address the principal developmental windows and organ systems relevant to the proposed paediatric ages, with no target-organ toxicity of concern identified beyond exaggerated pharmacology. On this basis a separate juvenile-animal toxicity study is not considered warranted; this position, and any focused developmental immune/gastrointestinal endpoints, will be confirmed with the agencies. If a specific paediatric concern were identified (for example relating to IL-22R-driven epithelial proliferation in a developing gut), a targeted non-human-primate assessment would be considered rather than a rodent study, which would not be pharmacologically informative.
• Studies not applicable to the modality. Consistent with ICH S6(R1) and the adult programme, standard genotoxicity and rodent carcinogenicity studies are not applicable to a monoclonal antibody, and no hERG assay or thorough-QT/dedicated QT study is warranted (no expectation of direct ion-channel interaction). These positions are unchanged for the paediatric development; the theoretical proliferative/neoplasia concern is managed clinically through long-term follow-up.

8. Age-appropriate quality and formulation

The paediatric quality strategy uses the same CHO-derived drug substance and the same control principles as the adult product (ICH Q5A(R2) viral safety, Q5C stability of biotechnological products, Q6B specifications), with formal comparability supporting any paediatric presentation. Because paediatric dosing is weight-based, the adult fixed-dose 150 mg and 300 mg devices are not, by themselves, adequate for the smaller/younger subsets. An age-appropriate presentation enabling accurate weight-band or body-weight dosing is proposed (for example a lower-strength pre-filled syringe suitable for graduated volumes), with attention to protein concentration, injectable volume and local tolerability, and to injection-site burden in children. Device human-factors evaluation will address caregiver administration for younger children and self-administration by adolescents. The pre-filled pen (autoinjector) is expected to be appropriate for older adolescents of adult-equivalent weight. The finalised paediatric formulation/presentation and its bridging to the adult product form part of the deferred measures.

9. Waiver request and justification

A full waiver of the entire paediatric population is not requested, because the condition (UC) occurs in the paediatric population and the mechanism is expected to be relevant to adolescents and older children.

A partial waiver (US) / product-specific waiver (EU) is requested for the subset birth to < 2 years, on the grounds that:

• the specific disease occurring in this subset (very-early-onset IBD) is a distinct entity, frequently monogenic, for which an agent targeting the polygenic TL1A/IL-22 mucosal biology of classic UC is unlikely to be safe or effective; and
• UC as characterised in the adult and older-paediatric population is very rare in this subset, such that a meaningful clinical study would be impossible or highly impractical.

No waiver is requested for the 2 to < 18-year subsets, in which the condition occurs and the mechanism is considered relevant; these subsets are addressed by study, subject to the deferral below.

10. Deferral request and justification

A deferral of the initiation and/or completion of the paediatric studies in the 2 to < 18-year subsets is requested. The justification is that:

• the product is ready for marketing authorisation in adults before the paediatric studies can be completed, and it is appropriate to make the adult product available without delay to the population in which the benefit-risk has been established;
• it is scientifically and ethically appropriate to establish the safety and efficacy of TILA-278 in adults, and to finalise the exposure-response understanding and the age-appropriate formulation, before exposing children; and
• the staged, older-to-younger design requires accruing PK/safety data from each subset to inform dosing in the next.

11. Planned studies, measures and milestones

Table PED.2 — Key binding elements / planned measures and indicative milestones (deferred)

Precise study-completion dates and the full set of key binding elements (design, endpoints, sample size, statistical/extrapolation methodology and the exposure-matching acceptance criteria) will be established in the agreed iPSP and in the PDCO opinion/PIP decision, and updated as adult and early paediatric data mature. The staged sequence allows each subset's dosing to be informed by the PK/safety data from the next-older subset.

12. Regulatory interactions and cross-references

This plan is intended to support agreement of the US iPSP with the FDA and adoption of a PDCO opinion / EU Decision on the PIP (including the requested waiver for birth to < 2 years and the deferral for 2 to < 18 years). It is consistent with, and cross-references, the adult efficacy and safety summaries (Modules 2.5, 2.7.3 and 2.7.4), the Risk Management Plan (which carries the paediatric development as an agreed PIP with deferral and reflects the long-term paediatric safety commitments), and the Development Safety Update Report. Any subsequent modification to the agreed measures, waiver or deferral will be handled through the applicable iPSP amendment and PIP-modification procedures and captured in the Change History of this document.