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Module 1 (EU) — Risk Management Plan (OBX-319)

Document ID: M1-RMP
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E2E

Risk Management Plan — OBX-319

This EU Risk Management Plan (RMP) presents the safety specification, the proposed pharmacovigilance activities, and the risk-minimisation measures for OBX-319, a humanised IgG1 anti-CD19 × anti-CD20 B-cell-depleting bispecific monoclonal antibody expressed in Chinese hamster ovary (CHO) cell culture and administered subcutaneously for the treatment of moderate-to-severe active Systemic Lupus Erythematosus (SLE). The plan is structured in accordance with ICH E2E and the EU good pharmacovigilance practices (GVP) Module V template, and is consistent with the reference safety information carried in the SmPC (Sections 4.3, 4.4, 4.6 and 4.8) and with the clinical safety database summarised in Module 2.7.4.

The safety concerns are derived from three sources: (i) the pharmacology of dual B-lineage depletion, which is on-target and mechanism-based; (ii) the non-clinical programme, in which the cynomolgus monkey is the sole pharmacologically relevant species under ICH S6(R1); and (iii) the pivotal Phase 3 study OBX319-301 (randomised N = 480; 162 OBX-319 High / 158 OBX-319 Low / 160 Placebo; 52 weeks of double-blind subcutaneous treatment on background standard-of-care). Product-quality-related considerations — CHO host-cell protein and DNA, Protein A leachate, size and charge variants, aggregates, and viral safety — are controlled under ICH Q5A(R2), Q5C and Q6B and enter this RMP only insofar as they inform clinical risk (principally the immunogenicity concern).

Part II — Safety Specification

The safety profile of OBX-319 (bispecific antibody) reflects its bispecific monoclonal antibody mechanism and the events observed in OBX319-301 (see Module 2.7.4). Immunogenicity: Anti-drug antibody (binding and neutralising) assessment is integral; immunogenicity may affect exposure and is characterised with a tiered validated assay strategy.

SI — Epidemiology of the indication and target population. SLE predominantly affects women of childbearing age (female-to-male ratio on the order of 9:1), most commonly presenting between the second and fourth decades of life. Moderate-to-severe active disease is associated with damage accrual (notably lupus nephritis), cumulative glucocorticoid toxicity, and increased mortality; infection is among the leading causes of death. The target population is therefore characterised by a high background rate of infection, compounded by concomitant standard-of-care immunosuppression (glucocorticoids and agents such as antimalarials, mycophenolate, azathioprine or methotrexate). This background must be borne in mind when interpreting the drug-attributable component of the infection-related safety concerns below.

SII — Non-clinical safety. Pivotal repeat-dose toxicology was conducted in the cynomolgus monkey, the sole pharmacologically relevant species, because OBX-319 does not cross-react with rodent CD19 or CD20; a rodent programme would not have been pharmacologically informative, consistent with the species-selection principles of ICH S6(R1). Subcutaneous repeat-dose studies produced the anticipated exaggerated pharmacology — sustained peripheral and lymphoid-tissue B-cell depletion with dose-dependent reductions in serum immunoglobulins — that was reversible during recovery, with no unexpected off-target organ toxicity. Tissue cross-reactivity and in-vitro cytokine-release assessments did not reveal binding to unexpected human tissues or a signal for cytokine-release syndrome. In line with ICH S6(R1), standard genotoxicity and carcinogenicity studies, dedicated hERG assays, and a thorough QT/QTc study were not conducted: these are not scientifically warranted for a large, non-genotoxic monoclonal antibody that does not distribute intracellularly and is not expected to interact with cardiac ion channels. Central-nervous-system, respiratory and cardiovascular safety-pharmacology endpoints were integrated into the repeat-dose design. The non-clinical findings translate into the clinical safety concerns of B-cell depletion (infection and hypogammaglobulinaemia) rather than into organ-specific toxicities.

SIII — Clinical trial exposure. The principal exposure derives from OBX319-301: 480 subjects randomised 1:1:1 to OBX-319 High (162), OBX-319 Low (158) or Placebo (160), each on background standard-of-care, with a mean baseline SLEDAI-2K of approximately 11 (moderate-to-severe active disease). Treatment-emergent adverse event and serious adverse event exposure by arm is summarised below (Module 2.7.4).

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 preferred terms were predominantly infections and administration-related events, consistent with the mechanism:

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

SIV — Populations not studied in clinical development. The pivotal programme excluded pregnant and breast-feeding women, patients with active serious or chronic infection (including active or latent tuberculosis and hepatitis B/C or HIV positivity), and patients with severe renal or hepatic impairment; live-vaccine recipients within the protocol-defined window were excluded, and enrolment of subjects aged ≥ 65 years was limited. There is no paediatric experience (addressed in the agreed paediatric investigation plan). Controlled exposure beyond 52 weeks is not yet available. These gaps are carried forward as missing information under SVII.

SV — Post-authorisation experience. OBX-319 is a new active substance with no post-authorisation exposure at the time of this initial RMP.

SVI — Additional EU requirements for the safety specification. The potential for medication error, off-label use, overdose, misuse for illegal purposes, and transmission of infectious agents was assessed. As a prescription-only biological administered subcutaneously under specialist supervision and subject to name-and-batch traceability (GVP), the potential for misuse or overdose is low; viral-safety controls under ICH Q5A(R2) address the theoretical risk of adventitious-agent transmission. No additional EU-specific safety concern is identified.

SVII — Identified and potential risks. OBX-319 simultaneously engages CD19 and CD20. Because CD19 is expressed across a broader window of B-cell ontogeny (from the pro-B stage through to plasmablasts) than CD20 (which is absent on the earliest progenitors and on terminally differentiated plasma cells), dual targeting captures escape populations that either specificity alone would miss and yields near-complete B-cell depletion. In OBX319-301 this manifested as a fall in circulating CD19+ B cells from approximately 210 to approximately 7 cells/µL on the active arms, with no meaningful change on placebo; anti-dsDNA titres declined and complement C3/C4 normalised in responders. The same pharmacology that drives efficacy also underlies the principal risks: profound depletion of antibody-producing lineages predisposes to infection and, with continued dosing, to hypogammaglobulinaemia.

Important identified risks

• Serious infections, including opportunistic infections — mechanism-based; reflected as the leading serious-event category and contraindicated in active serious infection (SmPC 4.3).
• Hypogammaglobulinaemia — cumulative reduction in serum immunoglobulins with sustained depletion, carrying a secondary infection risk that may warrant immunoglobulin monitoring.
• Injection-site reactions and systemic administration/hypersensitivity reactions — expected for a subcutaneously administered therapeutic antibody.

Important potential risks

• Progressive multifocal leukoencephalopathy (JC-virus opportunistic CNS infection) — a recognised class concern for profound and sustained B-cell depletion.
• Hepatitis B virus reactivation — in patients with resolved or occult infection, warranting screening before initiation.
• Immunogenicity (anti-drug antibodies) — binding and neutralising ADA may reduce exposure and efficacy or contribute to hypersensitivity; characterised by a tiered, validated assay strategy and informed by product-quality attributes (e.g., aggregates) under ICH Q6B.
• Reduced immune response to vaccination — diminished humoral response during depletion; live/attenuated vaccines are to be avoided.
• Malignancy — a theoretical long-term concern of prolonged immunomodulation, not observed in the controlled database.

Missing information

• Use in pregnancy and breast-feeding (IgG1 undergoes active placental transfer, principally in the second and third trimesters, with potential transient B-cell depletion in the neonate/infant).
• Long-term safety beyond 52 weeks of exposure.
• Use in the paediatric population.
• Use in patients with severe renal or hepatic impairment.
• Use in patients with active, chronic or latent infection.

Important identified/potential risks (class). Consistent with the immunomodulatory mechanism, serious and opportunistic infections are an important identified risk, and injection-site and hypersensitivity/immunogenicity reactions are expected; there is no boxed warning for the class. No boxed warning is warranted for OBX-319: the safety concerns are those of B-cell depletion and are adequately conveyed through routine labelling.

SVIII — Summary of the safety concerns.

Category	Safety concern
Important identified risks	Serious infections (including opportunistic infections); hypogammaglobulinaemia; injection-site and systemic administration/hypersensitivity reactions
Important potential risks	Progressive multifocal leukoencephalopathy; hepatitis B virus reactivation; immunogenicity (ADA); reduced response to vaccination; malignancy (long-term)
Missing information	Pregnancy and breast-feeding; long-term safety beyond 52 weeks; paediatric use; severe renal/hepatic impairment; use in active/chronic/latent infection

Part V — Risk Minimisation

Routine pharmacovigilance and routine risk-minimisation (labeling) are proposed; additional activities are introduced only where an important identified/potential risk warrants them.

Routine pharmacovigilance. Systematic adverse-reaction collection is supplemented by targeted follow-up questionnaires for serious/opportunistic infection, suspected progressive multifocal leukoencephalopathy, hypogammaglobulinaemia, and pregnancy outcomes. Signals are handled under the signal management process (GVP Module IX) and reported through the DSUR during development and the PSUR/PBRER post-authorisation. Immunogenicity is monitored via the tiered ADA assay strategy, with correlation to exposure and clinical events.

Routine risk minimisation. The following labelling measures apply:

• SmPC 4.3 (Contraindications): known serious hypersensitivity; active serious infection, including active tuberculosis.
• SmPC 4.4 (Special warnings and precautions): screen for infection, including tuberculosis and hepatitis B, before initiation; monitor for infection during treatment and interrupt/withhold as clinically indicated; consider serum immunoglobulin monitoring; avoid live/attenuated vaccines during B-cell depletion and complete recommended immunisations beforehand where feasible; remain vigilant for new neurological signs suggestive of progressive multifocal leukoencephalopathy.
• SmPC 4.6 (Fertility, pregnancy and lactation): advice reflecting IgG1 placental transfer and potential neonatal B-cell effects.
• SmPC 4.8 (Undesirable effects): infections, injection-site reactions, hypersensitivity and hypogammaglobulinaemia characterised as adverse reactions.
• Prescription-only supply under specialist care, with the Package Leaflet and biological name-and-batch traceability per GVP.

Additional pharmacovigilance and additional risk minimisation. The need for additional activities was assessed against each safety concern. A post-authorisation safety study — for example a pregnancy outcomes registry and/or a long-term safety cohort capturing serious infection, hypogammaglobulinaemia and malignancy beyond 52 weeks — is considered to address the corresponding missing information and potential risks. No safety concern currently requires additional risk-minimisation measures beyond labelling; a prescriber/patient educational programme would be introduced only if routine measures proved insufficient. The effectiveness of risk minimisation is evaluated through routine pharmacovigilance and periodic benefit-risk reporting.

ICH E2E.