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Development Safety Update Report (OBX-319)

Document ID: DSUR-001
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E2F

Development Safety Update Report (DSUR) — OBX-319

Annual DSUR for OBX-319: cumulative and interval safety across the development program, actions taken for safety reasons, line listings and summary tabulations of serious adverse events, and an overall safety assessment. ICH E2F.

OBX-319 is a humanized IgG1 anti-CD19 × anti-CD20 bispecific monoclonal antibody, produced in Chinese hamster ovary (CHO) cell culture and administered subcutaneously, under development by Virtual Biopharma Inc. for the treatment of moderate-to-severe active Systemic Lupus Erythematosus (SLE). The molecule depletes CD19+/CD20+ B lymphocytes through simultaneous dual-antigen engagement; its safety profile is therefore evaluated against the established profile of the B-cell-depleting therapeutic class. This DSUR consolidates the safety experience accrued in the clinical development program, together with relevant nonclinical and literature information, and provides the sponsor's integrated evaluation of the emerging risk profile.

1 Introduction

This DSUR has been prepared in accordance with ICH E2F to provide a comprehensive, thoughtful annual review and evaluation of the accumulated safety information for the investigational product OBX-319.

• Investigational product: OBX-319 (anti-CD19 × anti-CD20 bispecific monoclonal antibody; humanized IgG1; CHO-derived; subcutaneous administration).
• Sponsor: Virtual Biopharma Inc.
• Indication under development: moderate-to-severe active Systemic Lupus Erythematosus.
• Development International Birth Date (DIBD): 15 March 2021 (first authorization to conduct an interventional clinical trial).
• Reporting interval / data lock point (DLP): 15 March 2025 through 14 March 2026.
• Reference safety information (RSI): the current edition of the Investigator's Brochure in effect at the DLP.

The report covers the entire development program, which comprises the first-in-human single-ascending-dose study (OBX319-101), the multiple-ascending-dose study (OBX319-102), the Phase 2 dose-ranging study (OBX319-201), and the pivotal Phase 3 study OBX319-301, which completed its Week 52 primary analysis during the reporting interval. There are no marketed formulations of OBX-319; a Biologics License Application under 21 CFR 601 is in preparation/under review, and the product remains investigational worldwide. The scope of this DSUR is therefore the development program; post-marketing content (Sections 6.2 and 11) is not applicable.

2 Worldwide Marketing Approval Status

OBX-319 has not been granted marketing authorization in any country or region. It is investigational in all jurisdictions in which trials have been conducted. No approvals, withdrawals, refusals, or non-approvals for marketing occurred during the reporting interval. Regulatory interactions in the interval relate solely to the ongoing development program (US IND, EU clinical trial authorization, and MFDS IND in the Republic of Korea) and to preparation of the marketing application dossier.

3 Actions Taken in the Reporting Period for Safety Reasons

No actions were taken for safety reasons during the reporting interval that meet the ICH E2F reporting threshold. Specifically, during the interval there were:

• no refusal to authorize, or clinical hold, of any study for safety reasons;
• no suspension or early termination of an ongoing study for reasons of safety or lack of efficacy;
• no protocol modifications made in response to a safety signal (e.g., changes to dosing, monitoring, informed consent, study population, or exclusion criteria);
• no restrictions on distribution, dose limitations, or formulation changes introduced for safety reasons;
• no failure to obtain, or non-renewal of, a marketing authorization for safety reasons (the product is investigational).

Routine risk-management measures applied in the program — screening for and exclusion of active or chronic infection (including tuberculosis and hepatitis B and C), pre-treatment immunoglobulin quantitation, and protocol-defined guidance for management of injection-site and hypersensitivity reactions — reflect the anticipated class profile of a B-cell-depleting agent and were not introduced in response to an emergent signal during the interval.

4 Changes to Reference Safety Information

The RSI is the safety information section of the Investigator's Brochure. During the interval the Investigator's Brochure was updated to incorporate the completed Week 52 results of OBX319-301, including the observed adverse-event experience and the pharmacodynamic profile of B-cell depletion. The list of expected serious adverse reactions was reviewed and remains anchored on the class effects of B-cell depletion; the following continue to be characterized in the RSI:

• serious and opportunistic infections;
• hypogammaglobulinaemia / reductions in immunoglobulins associated with sustained B-cell depletion;
• injection-site reactions and hypersensitivity/systemic administration reactions;
• immunogenicity (anti-drug antibody formation) with potential impact on exposure.

No new adverse reaction was added to the list of expected events on the basis of interval data, and no expected event was removed. The updated RSI does not alter the overall risk characterization used elsewhere in this report.

5 Inventory of Clinical Trials Ongoing and Completed During the Reporting Period

Study	Phase	Design	Population	Status at DLP
OBX319-101 (SAD)	1	single-ascending-dose, randomized, placebo-controlled	Healthy participants	Completed (prior interval)
OBX319-102 (MAD)	1	multiple-ascending-dose, randomized, placebo-controlled	Healthy participants	Completed (prior interval)
OBX319-201	2	randomized, double-blind, placebo-controlled, dose-ranging	SLE (moderate-to-severe active)	Completed (prior interval)
OBX319-301	3	randomized, double-blind, placebo-controlled, 1:1:1, 52-week	SLE (moderate-to-severe active)	Completed during interval

OBX319-301 is the pivotal study and the principal source of interval safety data. It randomized 480 subjects (162 to the OBX-319 High-dose subcutaneous regimen, 158 to the OBX-319 Low-dose subcutaneous regimen, and 160 to placebo), all on background standard-of-care, with a mean baseline SLEDAI-2K of approximately 11. A full description of the design and results is provided in the clinical study report (CSR-301) and summarized in Modules 2.5 and 2.7. No new studies were initiated in the interval.

6 Estimated Cumulative Exposure

6.1 Cumulative Subject Exposure in the Development Program

Cumulative exposure since the DIBD is summarized below. Because the pivotal study completed during the interval, OBX319-301 contributes the great majority of both interval and cumulative person-time.

Study	Phase	Population	OBX-319 (active)	Placebo	Total
OBX319-101 (SAD)	1	Healthy	36	12	48
OBX319-102 (MAD)	1	Healthy	30	10	40
OBX319-201	2	SLE (moderate-to-severe)	90	30	120
OBX319-301	3	SLE (moderate-to-severe)	320	160	480
Total			476	212	688

Across the program, 476 subjects have received at least one dose of OBX-319 and 212 have received placebo (688 total). Subcutaneous exposure in the pivotal study was distributed across the High-dose (162) and Low-dose (158) regimens; cumulative person-time on active treatment is approximately 300 patient-years, driven by up to 52 weeks of on-study exposure in OBX319-301. Exposure was in adults with moderate-to-severe active SLE (Phase 2 and 3) and in healthy adult participants (Phase 1). Consistent with the pharmacology of an intact IgG1 and its target-mediated disposition, no dedicated exposure by intrinsic/extrinsic factor is presented here beyond the dose-group tabulation; population pharmacokinetic characterization is provided in Module 2.7.2.

6.2 Patient Exposure from Marketing Experience

Not applicable. OBX-319 is not marketed; there is no post-authorization exposure.

7 Data in Line Listings and Summary Tabulations

7.1 Reference Information

Adverse events were coded using MedDRA version 26.1 and are presented by System Organ Class and Preferred Term. Seriousness, causality (investigator assessment), and expectedness (against the RSI) were determined per protocol and the Safety Management Plan (TMF-006). OBX319-301 completed and was unblinded for the primary analysis; serious-event data are therefore presented by actual treatment received.

7.2 Line Listings of Serious Adverse Reactions During the Reporting Period

Serious adverse events occurring in the reporting interval are presented in the appended line listing (one row per event). Four subjects experienced a serious adverse event during the interval (OBX-319 High, 2; OBX-319 Low, 1; placebo, 1), consistent with the summary of safety (Modules 2.7.4 and ISS-301). The serious events are characterized as follows:

Treatment	Preferred term (MedDRA SOC)	Outcome	Investigator causality
OBX-319 High	Pneumonia (Infections and infestations)	Recovered/resolved with antibacterial therapy; dose interrupted	Related
OBX-319 High	Fatal cardiac event (Cardiac disorders)	Fatal (the single on-study death)	Not related
OBX-319 Low	Pyelonephritis (Infections and infestations)	Recovered/resolved	Related
Placebo	Lupus nephritis flare (Renal and urinary disorders)	Recovered/resolved	Not related (disease progression)

The two serious infections on active treatment were community-acquired bacterial infections that responded to standard therapy; neither was an opportunistic infection. The single death occurred in the OBX-319 High-dose arm and was assessed by the investigator as unrelated to study treatment, arising in a subject with pre-existing cardiovascular risk factors. The placebo serious event was an SLE disease-related flare.

7.3 Cumulative Summary Tabulations of Serious Adverse Events

The cumulative summary tabulation of serious adverse events by System Organ Class, across the development program, is presented below (subjects with events; blinded and unblinded data combined by actual treatment received). Serious events in the earlier-phase studies (OBX319-101/102/201) were sparse and none introduced a new category of concern; the cumulative picture is dominated by OBX319-301.

MedDRA System Organ Class	OBX-319 High	OBX-319 Low	Placebo
Infections and infestations	1	1	0
Cardiac disorders	1	0	0
Renal and urinary disorders	0	0	1
Total subjects with ≥1 SAE	2	1	1

These totals reconcile with the arm-level safety summary reported in Modules 2.7.4 and ISS-301 (serious adverse events in 2, 1, and 1 subjects and one death in the High-dose arm). No System Organ Class showed a clustering of serious events indicative of an unrecognized organ toxicity, and no dose-related pattern in serious events was evident.

8 Significant Findings from Clinical Trials During the Reporting Period

8.1 Completed Clinical Trials

OBX319-301 completed during the interval and is the principal source of new safety information. The overall adverse-event experience is summarized below.

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

The most frequently reported adverse events, by treatment arm, were:

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

The overall rate of subjects with at least one treatment-emergent adverse event was similar across the OBX-319 arms and placebo, consistent with a background of active SLE on standard-of-care. Infections were predominantly non-serious upper respiratory and urinary tract events, in keeping with the anticipated profile of B-cell depletion; the majority did not require treatment interruption. Injection-site reactions were more frequent on active treatment (High, 14; Low, 7; placebo, 6), were generally mild-to-moderate and self-limiting, and are an expected consequence of subcutaneous administration and immunogenicity. Notably, lupus nephritis flare was reported more frequently on placebo (16) than on OBX-319 (High, 4; Low, 8), consistent with disease control on active treatment rather than a treatment-emergent toxicity. Pharmacodynamically, the active arms produced near-complete depletion of circulating CD19+ B cells (from approximately 210 to approximately 7 cells/µL) that was not seen on placebo, accompanied by falling anti-double-stranded-DNA antibodies and normalization of complement C3/C4 in responders; these on-target effects underlie both the efficacy and the infection-related risk characterization.

8.2 Ongoing Clinical Trials

No interventional study was ongoing at the DLP; the pivotal study completed during the interval and the earlier-phase studies completed in prior intervals. No interim safety analysis from an ongoing blinded study is therefore reported.

8.3 Long-term Follow-up

Follow-up beyond the 52-week controlled period, including recovery of peripheral B cells and immunoglobulins after cessation of dosing and the durability of clinical response, is being characterized. Longer-term safety with repeated treatment remains an item of missing information (Section 19) to be addressed by continued follow-up and any planned extension experience.

8.4 Other Therapeutic Use of Investigational Drug

Not applicable. OBX-319 has not been used outside the sponsored clinical program (no expanded-access, named-patient, or compassionate-use exposure occurred in the interval).

8.5 New Safety Data Related to Combination Therapies

OBX-319 was administered on a background of standard-of-care for SLE (which may include antimalarials, corticosteroids, and immunosuppressants) rather than as a fixed combination product. No new safety concern attributable to concomitant immunosuppression — for example an unanticipated excess of serious infection with background therapy — was identified in the interval. The additive immunosuppressive potential of concomitant therapy is reflected in the infection risk characterization.

9 Safety Findings from Non-interventional Studies

Not applicable. No non-interventional (observational) study with OBX-319 was conducted or completed during the interval.

10 Other Clinical Trial/Study Safety Information

No additional clinical safety information (e.g., pooled analyses beyond the integrated summary, or safety data from third-party studies) was received in the interval that is not already reflected above. The integrated safety database (ISS-301) derives from OBX319-301.

11 Safety Findings from Marketing Experience

Not applicable. OBX-319 is not marketed; there is no spontaneous or post-authorization safety experience.

12 Non-clinical Data

No new nonclinical study was completed during the interval, and no new nonclinical finding altered the risk characterization. For context, the nonclinical safety package supporting the program is designed in accordance with ICH S6(R1) for biotechnology-derived pharmaceuticals:

• The cynomolgus monkey is the sole pharmacologically relevant species; OBX-319 does not cross-react with rodent CD19/CD20, so rodent toxicology is not scientifically informative and was not used to characterize toxicity.
• Repeat-dose toxicology in the cynomolgus monkey, with recovery periods, showed effects consistent with exaggerated pharmacology (reversible depletion of peripheral and tissue B cells) without unexpected target-organ toxicity; findings were reversible during the treatment-free recovery phase.
• Anti-drug antibody formation was monitored in the monkey and can influence exposure over time, consistent with the target-mediated disposition of the molecule.
• Consistent with ICH S6(R1), and because these assessments are not warranted for a monoclonal antibody, no genotoxicity, carcinogenicity, hERG, or thorough-QT (dedicated cardiac safety) studies were conducted; the standard small-molecule ICH S7A/S7B and E14 cardiac-safety batteries are not applicable to an intact IgG1. Reproductive/developmental assessment (including placental transfer considerations for an IgG1 in a population of women of childbearing potential) is addressed within the S6(R1)-based program.

Quality and comparability aspects for this CHO-derived bispecific antibody (viral safety, stability, and specifications) are handled under ICH Q5A(R2), Q5C, and Q6B in Module 3 and do not generate new safety findings for this report.

13 Literature

Published literature on the B-cell-depleting therapeutic class was reviewed for events of interest. The class experience continues to inform the risk characterization for OBX-319 and highlights, in particular: serious and opportunistic infections; hypogammaglobulinaemia with sustained B-cell depletion; rare progressive multifocal leukoencephalopathy (JC virus) as an important potential risk of profound B-cell/immune suppression; hepatitis B virus reactivation in previously infected individuals; and infusion/injection administration reactions and immunogenicity. No individual case report or aggregate publication in the interval described a new safety concern that is not already captured in the important-risks framework (Section 19) or the RSI.

14 Other DSURs

Not applicable. A single DSUR is prepared for the OBX-319 development program; no separate DSURs for other indications or formulations exist.

15 Lack of Efficacy

No signal of lack of efficacy of safety relevance was identified. In OBX319-301 the primary endpoint (SRI-4 response with low disease activity, SLEDAI-2K ≤ 4, at Week 52) was met, with response in 52.4% (76/145) on High-dose and 33.8% (49/145) on Low-dose versus 6.0% (9/150) on placebo, and the key secondary SLEDAI-2K LS-mean change favored active treatment (−6.37 High, −5.62 Low, −3.46 placebo; differences versus placebo −2.91 and −2.17). Lack of efficacy is therefore not a safety consideration for this population.

16 Region-Specific Information

The program is conducted under a US IND, an EU clinical trial authorization, and an MFDS IND in the Republic of Korea; corresponding regional Module 1 content (US, EU, and Korea) is included in the dossier. No region introduced a safety-related restriction during the interval. Regional cumulative summary tabulations and any region-specific expedited-reporting reconciliations, where requested, are provided as appendices. The marketing application (BLA under 21 CFR 601) relies on the same integrated safety database described here.

17 Late-Breaking Information

No late-breaking safety information with the potential to change the benefit-risk assessment was received between the DLP and the finalization of this report.

18 Overall Safety Assessment

18.1 Evaluation of the Risks

The accumulated data continue to support a risk profile that is consistent with the known effects of B-cell depletion and with subcutaneous antibody administration, and that is manageable within the studied population. The dominant, mechanistically expected risk is infection: in the controlled pivotal experience, infections were predominantly non-serious upper respiratory and urinary tract events; two serious infections occurred on active treatment (pneumonia; pyelonephritis), both community-acquired, non-opportunistic, and resolved with standard therapy. No opportunistic infection, no progressive multifocal leukoencephalopathy, and no hepatitis B reactivation were observed in the program. Injection-site reactions were more frequent on active treatment and were generally mild-to-moderate and self-limiting. Immunogenicity (anti-drug antibody formation) is characterized with a tiered, validated binding and neutralizing assay strategy and may affect exposure; it did not produce a distinct safety signal in the interval. Serious adverse events and the single death were infrequent, distributed across treatment groups, and without a dose-related pattern; the death was assessed by the investigator as unrelated to study treatment. There is no boxed warning for the class.

18.2 Benefit-risk Considerations

Within the reporting interval the benefit-risk balance of OBX-319 in moderate-to-severe active SLE remains favorable. Clinically meaningful benefit was demonstrated on the primary and key secondary endpoints (Section 15), underpinned by the intended pharmacology — near-complete circulating CD19+ B-cell depletion (approximately 210 to approximately 7 cells/µL) with reduction in anti-double-stranded-DNA antibodies and normalization of complement C3/C4 in responders. Against this benefit, the identified risks — chiefly infection, potential hypogammaglobulinaemia with sustained depletion, injection-site reactions, and immunogenicity — are foreseeable, monitorable, and addressable through screening, immunoglobulin monitoring, infection vigilance, and routine risk-minimization (labeling). No new information in the interval shifts this balance unfavorably.

19 Summary of Important Risks

The important risks and areas of missing information for OBX-319, consistent with the EU-RMP (M1-RMP) and the class profile, are summarized below.

Important identified risks.

• Serious and opportunistic infections (class effect of B-cell depletion).
• Hypogammaglobulinaemia / reduction in immunoglobulins with sustained B-cell depletion.
• Injection-site reactions and hypersensitivity/systemic administration reactions.
• Immunogenicity (anti-drug antibody formation), with potential impact on exposure.

Important potential risks.

• Progressive multifocal leukoencephalopathy (JC virus) associated with profound B-cell/immune suppression.
• Hepatitis B virus reactivation in previously infected individuals.
• Reduced immune response to vaccination during B-cell depletion.
• Malignancy with prolonged immunomodulation (theoretical).

Missing information.

• Long-term safety beyond 52 weeks and with repeated treatment, including the kinetics of B-cell and immunoglobulin recovery after cessation.
• Use in pregnancy and lactation (placental transfer of IgG1).
• Use in populations under-represented in the controlled experience (e.g., elderly; severe organ-threatening disease if excluded).
• Long-term impact of immunogenicity on efficacy and safety.

Routine pharmacovigilance and routine risk-minimization are proposed, with additional activities introduced only where an important identified/potential risk warrants them.

20 Conclusions

During the reporting interval the cumulative safety experience with OBX-319 — 476 subjects exposed to active treatment across the development program, with the pivotal study OBX319-301 completed — remained consistent with the anticipated profile of a CHO-derived anti-CD19 × anti-CD20 bispecific monoclonal antibody producing therapeutic B-cell depletion. No new safety signal was identified, no action was taken for safety reasons, and no change to the important-risks framework was warranted beyond incorporation of the pivotal results into the reference safety information. Serious events and the single (treatment-unrelated) death were infrequent and without a dose-related pattern. The benefit-risk balance in moderate-to-severe active SLE remains favorable, and the risk profile is manageable through routine pharmacovigilance and labeling. The sponsor will continue to monitor infection, immunoglobulin, and immunogenicity outcomes and to characterize long-term safety.

ICH E2F.