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Module 1 — Pediatric Study Plan (PSP/PIP) (OBX-319)

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) — OBX-319

The initial pediatric study plan (US iPSP) and EU paediatric investigation plan for OBX-319 in Systemic Lupus Erythematosus (moderate-to-severe active): 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.

OBX-319 is a humanized IgG1 anti-CD19 x anti-CD20 bispecific monoclonal antibody, produced in Chinese hamster ovary (CHO) cell culture and administered subcutaneously, that produces profound depletion of CD19-positive/CD20-positive B lineage cells. This plan sets out a single, harmonized pediatric strategy intended to satisfy both the US requirement for a pediatric assessment under PREA (with BPCA incentives where applicable) and the EU obligation to agree a paediatric investigation plan (PIP) with the Paediatric Committee (PDCO) under Regulation (EC) No 1901/2006. It defines the age groups for which a waiver is sought, the age groups for which studies are deferred, the extrapolation and pharmacokinetic/pharmacodynamic (PK/PD) bridging strategy, the proposed confirmatory pediatric study, the age-appropriate formulation, and the nonclinical and safety framework specific to B-cell-depleting therapy in a developing immune system.

1. Regulatory framework and scope

The condition under study — moderate-to-severe active SLE — is a serious, chronic, immune-mediated disease that occurs in the pediatric population as childhood-onset SLE (cSLE). Accordingly, SLE is not a condition for which a full product-specific waiver across the entire pediatric age range can be justified on epidemiological grounds, and it does not fall under an EU class waiver. The Sponsor (Virtual Biopharma Inc.) therefore proposes a combination of a partial waiver for the youngest age groups, in which the disease is absent or exceedingly rare and the benefit–risk of profound B-cell depletion is unfavorable, and a deferral of studies in the age groups in which cSLE occurs, so that the pivotal adult evidence and the adult safety database mature before pediatric exposure. The proposed indication for eventual pediatric labeling is moderate-to-severe active SLE on background standard-of-care, consistent with the adult program. Agreement on the iPSP will be sought at the End-of-Phase-2 interaction, and the PIP application will be submitted to the PDCO in parallel, with a single integrated set of measures presented to both regions to the extent permitted.

2. Condition and pediatric epidemiology (childhood-onset SLE)

SLE with onset before 18 years of age accounts for approximately 15–20% of all SLE and is well recognized clinically, but its distribution is strongly age-dependent: the disease is essentially not observed in neonates, infants, or toddlers, is rare below approximately 5 years of age, and rises through later childhood and adolescence, with a marked female predominance emerging around puberty. Compared with adult-onset disease, cSLE is characterized by higher disease activity at presentation, greater cumulative organ involvement (notably renal and hematologic), and greater dependence on corticosteroids and immunosuppressants, creating a clear unmet need for steroid-sparing, mechanism-based therapy. The pathophysiology of cSLE — loss of B-cell tolerance, autoantibody production (including anti-dsDNA), immune-complex formation, and complement consumption — is regarded as continuous with adult SLE, which is the scientific basis for the partial extrapolation strategy described in Section 5. This epidemiology directly supports waiving the youngest age groups (Section 4) while requiring a dedicated study in children and adolescents.

3. Product and mechanism relevant to the pediatric population

OBX-319 engages two B-lineage antigens (CD19 and CD20) simultaneously, yielding near-complete depletion of circulating CD19-positive B cells. In the adult pivotal study the pharmacodynamic effect was consistent and profound (peripheral CD19-positive B cells falling from approximately 210 to approximately 7 cells/µL on the active arms, with no change on placebo), accompanied by falling anti-dsDNA and normalization of complement C3/C4 in responders. Two features of the mechanism are especially relevant to pediatric development. First, target-mediated drug disposition (TMDD) links exposure to the size of the B-cell compartment; because B-cell mass, plasma volume, and body weight all differ in children, exposure–response cannot be assumed identical to adults and must be characterized (Section 5). Second, the immunologic consequence of the mechanism — suppression of humoral immunity during a life stage of active immune-system maturation and primary/booster immunization — is the central pediatric safety consideration and shapes both the age-group proposal and the risk-management measures (Sections 4 and 9).

4. Proposed age groups: waivers and deferrals

Using the ICH E11(R1) age categories, the Sponsor proposes the following:

• Preterm and term newborn infants (birth to 27 days), infants and toddlers (1 month to <2 years), and young children (2 to <5 years): product-specific waiver. SLE does not occur, or occurs only in exceptional case reports, in this range, so a study cannot be meaningfully conducted and would not offer a therapeutic benefit that outweighs the specific risks of profound, prolonged B-cell depletion during the period of primary immune-system development and the primary vaccination series. A waiver is therefore sought on the combined grounds that the disease does not occur in the specified age group and that the medicinal product is likely to be unsafe or lack significant therapeutic benefit relative to existing treatments in that group.
• Children (5 to 11 years) and adolescents (12 to <18 years): deferral of studies. cSLE occurs in these age groups, so a pediatric assessment is required rather than waived. Studies are deferred because it is appropriate to establish efficacy and adult safety before exposing children, and because premature initiation would delay availability of OBX-319 to adults. The deferral request is accompanied by the timelines in Section 11.

5. Extrapolation strategy and PK/PD bridging

The Sponsor proposes partial extrapolation of efficacy from the adult program to children aged 5 to <18 years, supported by confirmatory PK, PD, and safety data in the pediatric population, consistent with the ICH E11(R1) and pediatric-extrapolation frameworks. The scientific justification is that the disease course, the measured outcome (SLEDAI-2K and SRI-4-defined response), and, critically, the drug's mechanism are considered similar between adults and children with SLE. In the adult pivotal study, response tracked directly with the pharmacodynamic effect: SRI-4 with low disease activity (SLEDAI-2K ≤ 4) at Week 52 was achieved by 52.4% (76/145) on the High-dose arm and 33.8% (49/145) on the Low-dose arm versus 6.0% (9/150) on placebo, and the SLEDAI-2K least-squares mean change was −6.37 (High) and −5.62 (Low) versus −3.46 (placebo), corresponding to placebo-adjusted differences of −2.91 and −2.17. Because the same B-cell-depletion pharmacology drives these outcomes, near-complete CD19-positive B-cell depletion, together with reductions in anti-dsDNA and normalization of complement, serves as the mechanistic PD bridge to the pediatric population. Population PK/PD modeling and simulation — incorporating TMDD, body weight, and the pediatric B-cell compartment — will be used to select and confirm the pediatric dose(s) that reproduce the adult exposure and depletion associated with efficacy, thereby limiting the size and duration of the confirmatory pediatric study while preserving a clinically meaningful efficacy readout.

6. Proposed pediatric clinical study

A single confirmatory pediatric study is proposed for the deferred age groups (5 to <18 years), designed to establish dose, characterize PK/PD, and demonstrate efficacy and safety with reliance on the adult evidence via the extrapolation strategy above.

• Design: randomized, double-blind, placebo-controlled study on background standard-of-care, enrolling children (5 to 11 years) and adolescents (12 to <18 years) with moderate-to-severe active SLE. Weight-tiered subcutaneous dosing is used to match the adult High and Low exposure ranges (Section 7). Enrollment will be stratified to ensure representation of the pre-pubertal (5 to 11 years) and adolescent (12 to <18 years) subgroups.
• Objectives and endpoints: the primary objective couples the mechanistic PD bridge with clinical benefit — degree and durability of peripheral CD19-positive B-cell depletion, together with SRI-4/low-disease-activity response (SLEDAI-2K ≤ 4) assessed on the same instruments used in the adult pivotal study. Secondary endpoints include SLEDAI-2K change from baseline, anti-dsDNA and complement C3/C4, corticosteroid tapering, PK exposure metrics, immunogenicity (anti-drug antibodies, ADA), and growth and development.
• Sample size and analysis: the study is sized to characterize exposure–response and confirm the PD effect rather than to independently power a de novo efficacy claim, leveraging the partial-extrapolation framework; Bayesian borrowing from the adult data may be pre-specified. A long-term open-label safety follow-up is included to capture delayed effects on humoral immunity, infection, and immunoglobulin recovery.

7. Age-appropriate formulation and dosing

OBX-319 is a subcutaneous product; the same CHO-derived drug substance and liquid drug-product formulation used in adults are proposed for the pediatric program, avoiding a separate manufacturing process. Age-appropriateness is addressed at the level of delivery and dose selection rather than a new dosage form:

• Delivery device: the adult presentation (pre-filled syringe, with an autoinjector option for adolescents) is suitable for older children and adolescents and caregivers; deliverable volume, injection-site tolerability, and the option of caregiver administration are considered adequate for the 5-to-<18-year range and do not require a distinct pediatric dosage form.
• Dose selection: weight-based or weight-tiered subcutaneous dosing is proposed to reproduce, in children, the exposure and B-cell depletion associated with the adult High and Low regimens, as informed by the population PK/PD model (Section 5). Because TMDD links clearance to B-cell mass, dose banding by body weight is expected to control exposure variability across the pediatric weight range. Excipient exposure on a body-weight basis has been reviewed and is acceptable for the proposed age groups.

8. Nonclinical support (juvenile considerations)

The nonclinical package is governed by ICH S6(R1) for biotechnology-derived products and, for the pediatric assessment, ICH S11. The cynomolgus monkey is the sole pharmacologically relevant toxicology species because OBX-319 does not cross-react with rodent CD19/CD20; there is therefore no relevant rodent model for a juvenile toxicity study. Consistent with ICH S6(R1)/S11 and the standard expectations for monoclonal antibodies, the program does not include genotoxicity, carcinogenicity, hERG, or thorough-QT assessments, none of which are warranted for an antibody of this class. A dedicated juvenile animal toxicity study is not considered necessary to support the proposed pediatric population (5 to <18 years): the immune system is substantially developed by this age, the relevant target biology and B-cell-depletion pharmacology are already characterized in adult cynomolgus monkeys, and any residual pediatric-specific risk (effects on the maturing humoral immune response) is more directly and ethically informed by the clinical safety measures and immunoglobulin/immunization monitoring in Section 9 than by a juvenile NHP study. Because the youngest age groups are waived (Section 4), no juvenile nonclinical data are required to bridge to neonates or infants. Reproductive and developmental findings from the adult NHP program, and the effect of the antibody on the neonatal Fc receptor-mediated transfer and on B-cell ontogeny, inform pregnancy and lactation labeling and reinforce the waiver rationale for the youngest groups.

9. Pediatric safety management (class effects of B-cell depletion)

The identified and potential risks of OBX-319 are those of profound B-cell depletion, and each carries heightened importance in children:

• Serious and opportunistic infections: B-cell depletion increases susceptibility to serious and opportunistic infection. In the pediatric study, screening for and management of latent infections, antimicrobial prophylaxis where indicated, and structured infection surveillance are required; hepatitis B reactivation risk is managed per standard biologic practice.
• Hypogammaglobulinaemia: sustained depletion can lower immunoglobulin levels; because children have less immunologic reserve and may be building humoral memory, serial IgG (and IgM/IgA) monitoring before and during treatment, with pre-specified thresholds for evaluation and, if needed, immunoglobulin replacement, is built into the protocol. Recovery of B cells and immunoglobulins is a defined long-term follow-up endpoint.
• Immunization: age-appropriate vaccination, including any live vaccines, should be completed before initiating OBX-319 wherever feasible; live vaccines are to be avoided during B-cell depletion, and response to non-live vaccines may be attenuated. This requirement is emphasized more strongly than in adults given ongoing pediatric immunization schedules.
• Injection reactions and administration: local injection-site and systemic administration reactions are anticipated class effects and are managed with observation and standard measures appropriate to the age group.
• Growth and development: height, weight, pubertal staging, and, as appropriate, neurodevelopmental milestones are monitored, both as safety measures and because corticosteroid-sparing is a potential pediatric benefit.

Notably, there is no thyroid-related boxed warning for OBX-319; C-cell/thyroid signals are a consideration for a different pharmacologic class and are not applicable to a B-cell-depleting monoclonal antibody. The pediatric risk-management plan (EU RMP / US pharmacovigilance plan) will carry serious/opportunistic infection and hypogammaglobulinaemia as the key identified risks, with injection reactions and immunogenicity as anticipated risks, and will specify pediatric long-term follow-up for delayed immune effects.

10. Immunogenicity in the pediatric population

As with any therapeutic antibody, immunogenicity is relevant and is assessed in the pediatric study using the validated tiered ADA assay (screening, confirmatory, titer, and neutralizing-antibody characterization) applied in the adult program, with correlation to PK exposure, B-cell depletion, loss of PD effect, and safety events including injection/administration reactions. Pediatric ADA incidence, kinetics, and clinical impact are analyzed by age subgroup and factored into the population PK/PD model so that dose recommendations remain robust to any age-related differences in immunogenicity.

11. Deferral justification and development milestones

Deferral of the pediatric study in children and adolescents is justified so that the adult efficacy and safety database — anchored by the completed 52-week pivotal study OBX319-301 (randomized, double-blind, placebo-controlled, 1:1:1, N = 480: 162 High / 158 Low / 160 Placebo; baseline SLEDAI-2K approximately 11) — is available to inform pediatric dose selection, benefit–risk, and informed consent/assent before any child is exposed. The proposed milestones are:

• Milestone 1 — iPSP/PIP agreement: agreement of the iPSP with FDA and of the PIP with the PDCO, incorporating the partial waiver and deferral above.
• Milestone 2 — Model-informed pediatric dose: finalize the population PK/PD-derived pediatric weight-tiered dose(s) using adult data and simulation.
• Milestone 3 — Initiation of the pediatric study: first-patient-in for the confirmatory study in the 5-to-<18-year population, timed to the availability of the mature adult safety database.
• Milestone 4 — Completion and reporting: completion of the double-blind period and the long-term safety follow-up, with submission of the study report to both agencies.

The Sponsor will submit periodic PSP status updates to FDA and PIP compliance/modification requests to the PDCO as the program progresses, and will align the deferred-study timelines with the adult approval so that pediatric development proceeds without delaying access for adults.

12. Summary of proposed PSP/PIP measures

Age group (ICH E11 category)	Proposed measure	Basis
Preterm and term newborns (birth to 27 days)	Waiver	Disease does not occur; unfavorable benefit–risk of B-cell depletion
Infants and toddlers (1 month to <2 years)	Waiver	Disease does not occur; immune-development and immunization concerns
Young children (2 to <5 years)	Waiver	Disease exceedingly rare; benefit–risk unfavorable
Children (5 to 11 years)	Deferred study	cSLE occurs; partial extrapolation + PK/PD bridging
Adolescents (12 to <18 years)	Deferred study	cSLE occurs; partial extrapolation + PK/PD bridging

Clinical measure: one randomized, double-blind, placebo-controlled, weight-tiered subcutaneous study in the 5-to-<18-year population, with CD19-positive B-cell depletion and SRI-4/low-disease-activity (SLEDAI-2K ≤ 4) endpoints, PK/PD, immunogenicity, immunoglobulin monitoring, and growth/development, plus long-term safety follow-up.
Nonclinical measure: reliance on the adult cynomolgus-monkey package under ICH S6(R1)/S11; no juvenile animal study, and no genotoxicity, carcinogenicity, hERG, or thorough-QT studies, consistent with the monoclonal-antibody modality.
Quality measure: the pediatric program uses the same CHO-derived drug substance and subcutaneous drug product as the adult program, controlled under ICH Q5A(R2) (viral safety), Q5C (stability of biotechnological products), Q6B (specifications), and manufactured by Protein A capture with subsequent polishing chromatography; no separate pediatric dosage form is required. The BLA is filed under 21 CFR 601.
Formulation measure: age-appropriateness achieved through weight-tiered dosing and adolescent-suitable delivery (pre-filled syringe/autoinjector) rather than a new formulation.