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Integrated Summary of Safety (OBX-319)

Document ID: ISS-301
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH M4E(R2)

Integrated Summary of Safety — OBX-319

The integrated safety database for OBX-319 derives from OBX319-301 (safety set). OBX-319 is a humanized IgG1 anti-CD19 × anti-CD20 B-cell–depleting bispecific monoclonal antibody produced by Chinese hamster ovary (CHO) cell culture and administered subcutaneously; the integrated safety evaluation is therefore constructed around the pharmacology of profound, sustained peripheral B-cell depletion and the identified and potential risks characteristic of that mechanism. The pivotal randomized, double-blind, placebo-controlled study OBX319-301 (1:1:1 allocation, 52 weeks, on background standard-of-care in adults with moderate-to-severe active Systemic Lupus Erythematosus, baseline SLEDAI-2K approximately 11) contributes the integrated safety set of 480 treated subjects and essentially all controlled exposure at the intended commercial dose levels and subcutaneous route. The first-in-human single- and multiple-ascending-dose experience (CSR-101, CSR-102) and the clinical pharmacology program (population pharmacokinetics, target engagement, and immunogenicity) are supportive and are consistent with the pivotal findings. Consistent with ICH S6(R1), the sole pharmacologically relevant nonclinical toxicology species was the cynomolgus monkey, as OBX-319 exhibits no rodent target cross-reactivity; and because a monoclonal antibody of this class does not require the small-molecule safety modules, the integrated package intentionally contains no genotoxicity, carcinogenicity, hERG, or thorough-QT studies — none of which is warranted for a large-molecule biologic. Quality, viral-safety, stability, and specification aspects follow ICH Q5A(R2), Q5C, and Q6B, and the application is submitted as a Biologics License Application under 21 CFR Part 601.

Composition of the integrated safety database and pooling strategy — All 480 randomized subjects received at least one subcutaneous dose of study treatment and constitute the integrated Safety Analysis Set: 320 subjects were exposed to OBX-319 (162 at the High dose, 158 at the Low dose) and 160 to placebo, each on background standard-of-care throughout the 52-week double-blind period. Because the pivotal study contributes the controlled exposure at the intended dose levels and route, formal statistical pooling across studies was not required; adverse events were coded to a single MedDRA version and treatment-emergent adverse events (TEAEs) were summarised by randomised arm to preserve the controlled comparison. Exposure was balanced across arms, with the large majority of subjects in each group treated for the full 52 weeks (145 High, 145 Low, and 150 Placebo completing Week 52; 17, 13, and 10 discontinuing, respectively). This duration is adequate to characterise the lagged infection susceptibility and immunoglobulin decline anticipated with continuous, near-complete B-cell depletion, and to observe any late-emergent event such as delayed-onset neutropenia or immunogenicity.

Target engagement and pharmacodynamic context — On both active arms, subcutaneous OBX-319 produced near-complete depletion of circulating CD19+ B cells, from approximately 210 cells/µL at baseline to approximately 7 cells/µL, sustained through Week 52, whereas peripheral B-cell counts were essentially unchanged on placebo. Depletion was accompanied by a fall in anti-dsDNA antibodies and normalisation of complement C3/C4 among responders — pharmacodynamic correlates of disease control rather than adverse findings. OBX-319 displays target-mediated drug disposition (TMDD): systemic exposure is non-linear at low concentrations and is governed in part by the depleting B-cell mass, so the safety profile below is interpreted against a background of essentially complete and durable target engagement on both dose levels.

Overall adverse event summary — The proportion of subjects reporting at least one TEAE was similar across the three arms, with no excess on either active dose relative to placebo; the majority of events were mild to moderate in severity, non-serious, and did not require dose interruption.

Arm	N	≥1 TEAE	SAE	Deaths	Discontinued
OBX-319 High	162	78	2	1	17
OBX-319 Low	158	74	1	0	13
Placebo	160	78	1	0	10

Deaths — One death occurred over the 52-week double-blind period, in the OBX-319 High arm (1 High, 0 Low, 0 Placebo). Consistent with the identified infection risk of profound B-cell depletion, the fatal event was a serious infection in a subject with active lupus receiving background immunosuppression; it was reviewed by the investigator and the sponsor and managed with standard care. No fatal events occurred on the OBX-319 Low or placebo arms.

Serious adverse events — Serious adverse events were infrequent and comparable across arms (2 High, 1 Low, 1 Placebo), without a dose-related pattern. Serious events were predominantly serious infections, in line with the pharmacology of B-cell depletion; one of the two serious events in the High arm had the fatal outcome described above, and the remaining serious events resolved with treatment. No unexpected serious event attributable to the anti-CD19 × anti-CD20 bispecific mechanism was identified.

Discontinuations — Forty subjects discontinued study treatment before Week 52 (17 High, 13 Low, 10 Placebo), corresponding to high completion in all arms (145/162 High, 145/158 Low, 150/160 Placebo). Discontinuations did not show a treatment-related pattern indicative of a specific tolerability concern; reasons included adverse events, withdrawal of consent, and lack of efficacy, the last being more relevant on placebo.

Most frequent adverse events (subjects, by arm)

Preferred term	OBX-319 High	OBX-319 Low	Placebo
Upper respiratory tract infection	25	18	13
Urinary tract infection	16	14	14
Nasopharyngitis	11	14	16
Headache	11	11	16
Lupus nephritis flare	4	8	16
Injection site reaction	14	7	6

Interpretation of common events — The most frequently reported events were infections of the upper respiratory and urinary tracts and nasopharyngitis, consistent with the expected profile of a B-cell–depleting agent; these were predominantly mild-to-moderate and non-serious. Lupus nephritis flare was reported more frequently on placebo (16) than on OBX-319 Low (8) or High (4) — an inverse, dose-ordered gradient that reflects disease control by active treatment rather than a drug-related adverse effect, and is concordant with the efficacy findings. Injection site reactions showed a dose-ordered incidence (14 High, 7 Low, 6 Placebo) in keeping with subcutaneous administration; these were generally mild, transient, and localised, and did not lead to treatment discontinuation. Headache and nasopharyngitis were balanced or numerically higher on placebo and are not considered treatment-related.

Serious and opportunistic infections (important identified risk) — Serious and opportunistic infections are the principal identified risk of B-cell depletion and were designated an adverse event of special interest. The overall infection burden was dominated by non-serious upper respiratory and urinary tract infections and nasopharyngitis; the incidence of serious infection was low, and serious infections accounted for the small number of serious adverse events and the single fatal event described above. No cases of progressive multifocal leukoencephalopathy, tuberculosis reactivation, or hepatitis B virus reactivation were reported over the 52-week period. Screening for latent tuberculosis and for hepatitis B and C was performed at entry, live and attenuated vaccines were prohibited during treatment, and protocol-directed surveillance for serious and opportunistic infection was applied throughout — measures that are carried forward as central elements of the routine risk-management strategy.

Hypogammaglobulinaemia and immunoglobulins (important identified risk) — Consistent with the mechanism, mean serum immunoglobulin concentrations declined modestly from baseline on the active arms — most notably IgM, with smaller changes in IgG — while remaining, for most subjects, at or near the normal range; a minority developed immunoglobulin values below the lower limit of normal without an associated increase in serious infection over the controlled period. Immunoglobulins (IgG, IgM, IgA) are monitored as part of routine safety follow-up, and persistent hypogammaglobulinaemia is retained as an important identified risk requiring continued characterisation in longer-term treatment.

Injection-site and administration reactions — Local injection site reactions were the most characteristic administration-related events and showed the dose-ordered incidence tabulated above; systemic administration and hypersensitivity reactions were infrequent and non-serious, and no anaphylaxis was reported. This pattern is consistent with subcutaneous delivery of a humanized IgG1 and did not necessitate premedication or discontinuation.

Haematology — Absolute neutrophil counts were monitored given the potential for cytopenias, including late-onset neutropenia, with B-cell–depleting antibodies. No clinically significant neutropenia or associated serious infection was identified over the 52-week period.

Immunogenicity (anti-drug antibodies) — Anti-drug antibodies (binding and neutralising) were assessed using a tiered, validated assay strategy (screening, confirmatory, titre, and neutralising-antibody tiers) applied to samples from OBX319-301, in line with ICH M10 bioanalytical expectations. Observed immunogenicity was low-level and did not have a clinically meaningful impact on exposure, efficacy, or safety, consistent with a humanized IgG1. Because immunogenicity can alter the exposure of a TMDD-governed antibody, ADA status was integrated into the population pharmacokinetic and safety analyses; detailed results are provided in Module 2.7.2 and the immunogenicity summary report (IMMUNO-001).

Laboratory, vital signs, and cardiac safety — Beyond the intended on-target reduction in CD19+ B cells (approximately 210 → approximately 7 cells/µL) and the associated fall in anti-dsDNA antibodies and normalisation of complement C3/C4 among responders, no new or clinically important laboratory, vital-sign, or electrocardiographic signal was identified. Consistent with ICH guidance for biotechnology-derived pharmaceuticals, a dedicated thorough-QT study and hERG assessment are not warranted for a monoclonal antibody, and no cardiac repolarisation signal was observed on routine electrocardiographic monitoring.

Malignancy — No clustering of malignant events was observed over the 52-week controlled period. Given the immunomodulatory mechanism, malignancy is retained as an important potential long-term risk to be further characterised in continued treatment and post-marketing pharmacovigilance.

Special populations, intrinsic and extrinsic factors, and drug interactions — SLE affects predominantly women of childbearing potential; effective contraception was required during treatment, and because IgG1 antibodies undergo active placental transfer in the second and third trimesters, pregnancy and neonatal B-cell considerations are addressed in product labelling and the risk-management plan. As a large-molecule antibody eliminated by proteolytic catabolism rather than renal or hepatic pathways, OBX-319 is not expected to require dose adjustment for renal or hepatic impairment, and it does not undergo cytochrome P450–mediated metabolism, so a direct pharmacokinetic drug–drug interaction is not anticipated; the theoretical potential for disease-related normalisation of cytokines to affect CYP substrates is of low clinical relevance for a B-cell–depleting agent. Concomitant immunosuppression may compound the infection risk of the class and is reflected in monitoring recommendations. No safety signal warranting a dedicated intrinsic- or extrinsic-factor restriction beyond these considerations was identified.

Absence of a thyroid warning — The safety profile carries no thyroid C-cell or medullary thyroid carcinoma boxed warning; that labelling is specific to the glucagon-like peptide-1 receptor agonist class and is not applicable to a B-cell–depleting bispecific antibody. No thyroid-related safety signal was observed in the integrated database.

Risk-management context — The important identified risks (serious and opportunistic infections; hypogammaglobulinaemia) and important potential risks (malignancy; immunogenicity-related effects on exposure) are managed through routine pharmacovigilance, protocol-directed screening and surveillance, immunoglobulin and haematology monitoring, and prohibition of live/attenuated vaccines during treatment, as detailed in the risk-management plan and associated regional documents.

Adverse events were consistent with the bispecific monoclonal antibody class; serious events were infrequent. Immunogenicity: Anti-drug antibody (binding and neutralising) assessment is integral; immunogenicity may affect exposure and is characterised with a tiered validated assay strategy. Overall, across the 52-week integrated database, OBX-319 was generally well tolerated at both dose levels, with a TEAE incidence comparable to placebo, infrequent serious adverse events and deaths without a meaningful dose-related pattern, and a profile dominated by the anticipated class effects — infections, injection site reactions, modest immunoglobulin decline, and low-level immunogenicity — each addressed by the routine monitoring and risk-management strategy; no safety signal specific to the active treatment or to the anti-CD19 × anti-CD20 bispecific mechanism was identified. ICH M4E(R2) §5.3.5.3. Cross-references: M2.7.4 (summary of clinical safety), M2.7.2 (clinical pharmacology, immunogenicity), M2.6 (nonclinical summaries), M2.5.6 (benefit–risk); ICH E3, S6(R1), M10, Q5A(R2), Q5C, Q6B; 21 CFR Part 601.