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SEND / Nonclinical Data Reviewer's Guide (OBX-319)

Document ID: SEND-001
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): CDISC SEND

SEND / Nonclinical Data Reviewer's Guide — OBX-319

Orients the reviewer to the standardised nonclinical (SEND) datasets for OBX-319: the studies represented, dataset structure and controlled terminology, and conformance notes, providing traceability from the toxicology study reports to the submitted data. CDISC SEND; ICH.

1. Purpose and Scope

This Nonclinical Study Data Reviewer's Guide (nSDRG) is the human-readable companion to the Standard for Exchange of Nonclinical Data (SEND) datasets submitted in support of OBX-319 (a humanised IgG1 anti-CD19 x anti-CD20 bispecific monoclonal antibody, produced by recombinant Chinese hamster ovary (CHO) cell culture, administered subcutaneously) for moderate-to-severe active Systemic Lupus Erythematosus (SLE). It follows the PhUSE nSDRG template and the recommendations of the FDA Study Data Technical Conformance Guide. Its purpose is to describe what SEND data are provided, how they map to the pivotal toxicology study reports in Module 4.2.3, which study data are deliberately absent (and why), how the modality-specific endpoints of a B-cell-depleting biologic are represented within the SEND model, and the disposition of the data-conformance findings raised by the validator.

The datasets are submitted to support the Biologics License Application (21 CFR Part 601). SEND applies to this application under the FDA Data Standards Catalog; the underlying nonclinical program was designed under ICH S6(R1) (biotechnology-derived pharmaceuticals) and ICH M3(R2), with quality attributes controlled per ICH Q5A(R2), Q5C, and Q6B (Module 3). The datasets themselves make no efficacy claim; they carry the individual-animal source data underlying the integrated no-observed-adverse-effect level (NOAEL) and exposure margins presented in Module 4.2.3.

2. Study Data Standards and Dictionary Versions

A single, internally consistent set of standards versions was applied across all studies represented in SEND.

Component	Version / package
SEND Implementation Guide (general toxicology, single-dose, cardiovascular/respiratory safety pharmacology)	SENDIG v3.1.1
SEND Implementation Guide — Developmental and Reproductive Toxicology (ePPND)	SENDIG-DART v1.1
Controlled Terminology	SEND Controlled Terminology (NCI EVS, quarterly package)
Data-definition file	Define-XML v2.0 (with stylesheet)
Validation engine / rules	Pinnacle 21 executing the FDA Validator Rules and CDISC SEND conformance rules
Submission framework	FDA Study Data Technical Conformance Guide; FDA Data Standards Catalog; eCTD (21 CFR 601)

No pathology or event dictionary of the MedDRA type is used for these nonclinical datasets; macroscopic and microscopic findings are coded to SEND Controlled Terminology (anatomical location, morphology/severity), supplemented by sponsor-defined terms where no published term exists (Section 8).

3. Nonclinical Studies and Their SEND Representation

The pivotal nonclinical program in the cynomolgus monkey — the sole pharmacologically relevant species, as OBX-319 does not cross-react with the rodent CD19/CD20 orthologues — is represented in SEND as follows.

Study	Design	Species / route	Duration	SENDIG	eCTD location of report
OBX319-TX-001	Repeat-dose toxicity + integrated TK	Cynomolgus monkey / subcutaneous	4 weeks + recovery	v3.1.1	m4 / 4.2.3.2
OBX319-TX-002 (pivotal)	Repeat-dose toxicity + integrated TK + safety-pharmacology endpoints	Cynomolgus monkey / subcutaneous	up to 26 weeks + recovery	v3.1.1	m4 / 4.2.3.2
OBX319-RP-001	Enhanced pre- and post-natal development (ePPND)	Cynomolgus monkey / subcutaneous	per ICH S5(R3)/S6(R1)	DART v1.1	m4 / 4.2.3.5

Core safety-pharmacology endpoints (cardiovascular, respiratory, and central-nervous-system observations) were embedded in the repeat-dose studies rather than conducted as standalone studies, so no freestanding safety-pharmacology dataset exists; these endpoints appear as the CV, EG, RE, VS, and CL domains within OBX319-TX-002 (Section 7.4).

4. Data and Studies Not Represented in SEND (with Rationale)

The reviewer should not expect certain datasets; their absence is by design and reflects the modality, not an omission.

• No rodent general-toxicity, PK, or TK datasets. There is no rodent cross-reactivity to the human CD19/CD20 epitopes; rodent studies would be pharmacologically uninterpretable, so none were conducted and none are submitted (ICH S6(R1)).
• No Tumor Findings (TF) domain and no carcinogenicity dataset. A conventional rodent carcinogenicity bioassay was not conducted; carcinogenic potential was addressed by a weight-of-evidence assessment (Module 2.6.6.5 / 4.2.3.3). SEND therefore contains no carcinogenicity study and no TF domain.
• No genotoxicity data. Genotoxicity is not applicable to a large recombinant protein that does not interact directly with DNA (ICH S2 waiver); genotoxicity is outside the SEND standard in any case.
• No hERG / thorough-QT dataset. A monoclonal antibody does not engage cardiac ion channels; the ICH S7B/E14 assessment is waived and cardiovascular electrophysiology is instead captured as EG (corrected QT) within OBX319-TX-002.
• Tissue cross-reactivity (Study OBX319-TC-001) is not in SEND. This is an in vitro immunohistochemistry study on human and cynomolgus monkey tissue panels; the SEND model does not cover in vitro immunohistochemistry, so the study is provided as its report only (Module 4.2.1 / 2.6.2.3). Its finding — membrane binding restricted to the expected B-lymphoid distribution with no unexpected reactivity — is narrative, not tabulated.

5. Trial Design Datasets

Each study directory carries the full trial-design model so the reviewer can reconstruct arms, elements, and set membership without reference to the report.

Domain	Content for OBX-319 studies
TS	Trial Summary parameters: species (Macaca fascicularis), route (subcutaneous), test article, SENDIG version, study duration/type, and design characteristics.
TA / TE	Trial Arms and Trial Elements describing the treatment epoch and the treatment-free recovery epoch for the main-study and recovery cohorts.
TX	Trial Sets linking dose group and cohort (control, low, intermediate, high; main study and recovery; toxicokinetic/satellite subsets) to SETCD.
DM	One record per animal, with SPECIES/STRAIN, SEX, ARMCD/SETCD, and age/weight at start; both sexes are represented in each dose group.
SE	Subject Elements documenting each animal's passage through the treatment and recovery epochs.
CO	Free-text comments cross-referenced to the individual-animal source records.

Dose groups comprise a vehicle control plus ascending OBX-319 dose levels; the specific mg/kg levels, group sizes, and the resulting NOAEL and AUC/Cmax margins over the clinical dose levels evaluated in OBX319-301 are reported in Module 4.2.3 and are not restated here.

6. Subject-Level Datasets Submitted

The pivotal repeat-dose study (OBX319-TX-002) carries the full complement of findings domains expected for a chronic monkey toxicity study; the 4-week study (OBX319-TX-001) carries the same domains at its shorter duration; the ePPND study (OBX319-RP-001) uses the SENDIG-DART structure (Section 7.5).

Domain	Domain name	Modality-relevant content
EX	Exposure	Subcutaneous administration; dose, dose units, frequency, and injection site per animal.
BW / BG	Body Weights / Body Weight Gain	Serial body weights and derived gains.
FW	Food and Water Consumption	Consumption over the dosing and recovery epochs.
CL	Clinical Observations	General observations, injection-site observations, and functional/neurobehavioural (CNS) observations.
LB	Laboratory Test Results	Haematology, clinical chemistry, coagulation, urinalysis; serum immunoglobulins (IgG, IgM, IgA); B-cell immunophenotyping by flow cytometry; and anti-drug antibody results (Sections 7.1–7.2).
OM	Organ Measurements	Organ weights, including lymphoid organs (spleen, thymus, lymph nodes).
MA	Macroscopic Findings	Terminal and recovery necropsy observations.
MI	Microscopic Findings	Histopathology, including depletion of B-cell zones (germinal centres, follicles) in spleen, lymph nodes, and gut-associated lymphoid tissue.
PM	Palpable Masses	In-life masses, where observed.
DD	Death Diagnosis	Cause/manner for any unscheduled deaths.
CV / EG / RE / VS	Cardiovascular / ECG / Respiratory / Vital Signs	Embedded safety-pharmacology endpoints (Section 7.4).
PC / PP	PK Concentrations / PK Parameters	Toxicokinetics under target-mediated disposition (Section 7.3).
RELREC, SUPP--, POOLDEF	Relationship and supplemental datasets	Record-level relationships, supplemental qualifiers, and any toxicokinetic sample pooling definitions.

7. Modality-Specific Data Handling

Several endpoints that are central to a B-cell-depleting bispecific antibody have no dedicated domain in SENDIG v3.1.1. Their placement within the model is documented here so the reviewer can locate them.

7.1 B-cell immunophenotyping (flow cytometry). Near-complete depletion of circulating B cells is the primary pharmacodynamic readout of the study and the on-target driver of the toxicology. Flow-cytometry immunophenotyping — absolute and relative CD19+ and CD20+ B-cell counts, with CD3+ T cells and other lineages as specificity controls — is represented in LB with a sponsor-defined category (LBCAT = "IMMUNOPHENOTYPING") and sponsor test codes for each marker, cross-referenced in Define-XML. There is no separate immunophenotyping domain in the standard; this LB placement follows the Technical Conformance Guide approach for endpoints outside published Controlled Terminology.

7.2 Anti-drug antibodies / immunogenicity. ADA were sampled concurrently with the toxicokinetic schedule and evaluated with a tiered strategy (screen, confirm, titre, and neutralising assay). Results are represented in LB under a sponsor-defined category (LBCAT = "ANTI-DRUG ANTIBODY") with the screen/confirm/titre outcomes, and are related to the affected PC/PP records via RELREC and SUPP-- so that any exposure decrement can be interpreted against ADA status. Nonclinical ADA in the cynomolgus monkey are used only to interpret animal exposure and are not predictive of, or extrapolated to, clinical immunogenicity for a humanised antibody.

7.3 Toxicokinetics and target-mediated disposition (PC / PP). Serum OBX-319 concentrations (PC) were measured by a validated ligand-binding assay; derived parameters (PP) include Cmax, Tmax, AUC over the dosing interval, and the accumulation ratio. Consistent with target-mediated drug disposition, exposure rises less than dose-proportionally at low concentrations and approaches dose-proportionality once the target-mediated clearance component is saturated; this non-linearity, and any ADA-associated exposure loss, is flagged in supplemental qualifiers and comments rather than altering the tabulated values. Classical small-molecule ADME (mass balance, CYP/transporter) is not applicable to an intact IgG and generates no datasets.

7.4 Safety-pharmacology endpoints (CV / EG / RE / VS / CL). Cardiovascular (blood pressure, heart rate), electrocardiographic (including corrected QT), respiratory (rate and pattern), and central-nervous-system observations were captured within OBX319-TX-002 and populate the CV, EG, RE, VS, and CL domains. No standalone safety-pharmacology study, hERG assay, or thorough-QT study was performed, so no corresponding standalone dataset exists.

7.5 Enhanced pre- and post-natal development (SENDIG-DART). OBX319-RP-001 is represented using SENDIG-DART v1.1. Maternal data (exposure, in-life, and outcome) and F1 offspring data (including infant peripheral B-cell counts, lymphoid development, and post-natal reconstitution) are provided to the extent the DART model supports the ePPND design; design elements not covered by the standard are described in the study report (Module 4.2.3.5). IgG placental transfer, greatest in the second and third trimesters, motivates the offspring B-cell endpoints, which are the reproductive-toxicology expression of the same on-target pharmacology.

8. Controlled Terminology, Sponsor Extensions, and Units

SEND Controlled Terminology is applied throughout; extensible codelists were extended, and non-extensible codelists were not. Sponsor-defined terms are confined to endpoints without published Controlled Terminology and are declared in Define-XML:

• Immunophenotyping and ADA test codes/names in LB (Sections 7.1–7.2), with their categories, specimen types, and result units.
• Any assay-specific units for serum immunoglobulins and for the ligand-binding PK assay, mapped to standard unit terms where these exist.

Anatomical locations and morphologic findings in MA/MI use SEND Controlled Terminology for specimen and finding, with severity graded on the standard scale; sponsor terms are used only where no published term applies and are traceable through Define-XML.

9. Define-XML, Directory Structure, and File Inventory

Each study is submitted as a self-contained SEND package: the SAS transport (XPT) datasets, a Define-XML v2.0 data-definition file with its stylesheet, and this reviewer's guide referenced at the study level. Datasets are placed in the eCTD under Module 4 alongside the corresponding study report (m4 / 4.2.3), one directory per study (OBX319-TX-001, OBX319-TX-002, OBX319-RP-001). Define-XML documents dataset- and variable-level metadata, value-level metadata for the multi-test LB domain (haematology, chemistry, immunoglobulins, immunophenotyping, ADA), the origin of each variable, and all sponsor codelist extensions, providing the traceability path from the study report tables back to the individual-animal records.

10. Data Conformance and Validation Findings

All datasets were validated with Pinnacle 21 against the FDA Validator Rules and CDISC SEND conformance rules at the versions in Section 2. There are no Reject-severity findings and no unresolved Error-severity findings. The remaining Warning/Notice-level findings and their disposition are summarised below; each is an expected consequence of the modality or the study design, not a data defect.

Category	Finding	Disposition / rationale
Sponsor-defined terminology	LB test codes/names for immunophenotyping and ADA are not present in SEND Controlled Terminology	Expected; no published Controlled Terminology exists for these endpoints. Extensible codelist extended and fully declared in Define-XML (Sections 7.1–7.2, 8).
Subjects without records in some optional domains	Toxicokinetic/satellite animals lack certain in-life findings records	Expected by design; satellite animals contribute PC/PP (and ADA) only. Set membership is defined in TX/DM.
Non-linear exposure vs dose	PP exposure metrics increase less than dose-proportionally at low doses	Expected pharmacology (target-mediated disposition), not a data error; annotated in SUPP--/CO (Section 7.3).
Absent domains	No TF (Tumor Findings); no carcinogenicity, genotoxicity, or standalone safety-pharmacology datasets	By design for this modality (Section 4).
Species scope	No rodent studies present	By design; no rodent cross-reactivity (Section 4).

No conformance finding affects the integrity of the tabulated results or the derivation of the NOAEL and exposure margins.

11. Traceability to the Toxicology Study Reports

The SEND datasets are the individual-animal source for the summary tables in the toxicology study reports. The repeat-dose datasets (OBX319-TX-001, OBX319-TX-002) underlie the repeat-dose toxicity narrative and the integrated NOAEL and AUC/Cmax margins in Module 4.2.3.2/4.2.3.3; the PC/PP domains underlie the toxicokinetic exposures cited in Module 4.2.2 and 2.6.4; the immunophenotyping, immunoglobulin, and microscopic lymphoid-depletion records underlie the on-target B-cell-depletion and hypogammaglobulinaemia findings; and the ePPND datasets (OBX319-RP-001) underlie the reproductive-toxicology narrative in Module 4.2.3.5/2.6.6.6. The tissue cross-reactivity finding (OBX319-TC-001) is traceable to its report only, as it is outside the SEND model (Section 4). Define-XML provides the variable-level path from each report table to the contributing dataset and records.

12. Regional Submission Notes

SEND datasets are provided in the applications where they are required or accepted — the FDA BLA (21 CFR 601) per the Data Standards Catalog, and the corresponding PMDA-format submission. The EU (EMA) and MFDS dossiers do not require SEND; for those regions the nonclinical evidence is conveyed through the Module 2.6 summaries and the Module 4 study reports, and this reviewer's guide accompanies the datasets wherever they are filed.

Governing standards: CDISC SENDIG v3.1.1, SENDIG-DART v1.1, SEND Controlled Terminology, Define-XML v2.0; FDA Study Data Technical Conformance Guide; ICH M3(R2), S6(R1), S5(R3), S7A; S2/S1/S7B addressed by waiver rationale.