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Module 1 (EU) — Summary of Product Characteristics (OBX-319)

Document ID: M1-EU
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): QRD / 2001/83/EC

EU Summary of Product Characteristics (SmPC) — OBX-319

4.1 Therapeutic indications. OBX-319 is indicated for the treatment of adult patients with moderate-to-severe active, autoantibody-positive Systemic Lupus Erythematosus (SLE) who have responded inadequately to standard-of-care therapy. OBX-319 is used in addition to background standard-of-care. Patients enrolled in the pivotal programme had clinically and serologically active disease, characterised by an elevated SLEDAI-2K together with autoantibody positivity (raised anti-double-stranded DNA [anti-dsDNA] antibodies) and/or low complement (C3/C4); the greatest benefit was observed in patients with this profile.

4.2 Posology and method of administration. Treatment with OBX-319 should be initiated and supervised by physicians experienced in the diagnosis and treatment of SLE. OBX-319 is administered by subcutaneous injection. Two dose regimens (a higher and a lower dose) were evaluated in the pivotal study; the recommended regimen is that reflected in the approved product information, continued as long as clinical benefit is maintained. Clinical experience is based on continuous treatment over 52 weeks on a background of standard-of-care.

Pre-treatment evaluation. Before initiating OBX-319, patients should be screened for active and latent infection, including tuberculosis (TB), and for hepatitis B and hepatitis C, in accordance with local guidance; active serious infection must be resolved before starting treatment (see section 4.3). Because OBX-319 produces profound and sustained depletion of circulating B cells, immunisation status should be reviewed and any required live or non-live vaccinations completed before treatment where feasible; live vaccines are not recommended during B-cell depletion. Baseline serum immunoglobulins (IgG, IgM, IgA) should be measured.

Monitoring during treatment. Patients should be monitored for signs and symptoms of infection during and after treatment, including opportunistic infection. Serum immunoglobulins should be monitored periodically; persistent hypogammaglobulinaemia may warrant additional clinical assessment (see section 5.1). B-cell recovery is expected to lag behind the last dose owing to the depth of depletion. Patients should be observed for injection-related and hypersensitivity reactions; premedication (e.g., an antihistamine, antipyretic and/or corticosteroid) may be considered per institutional practice, and appropriate management for hypersensitivity should be available.

Missed dose. A missed dose should be administered as soon as possible, after which the regular schedule is resumed.

Special populations. No dose adjustment is required on the basis of age, mild-to-moderate renal impairment, or mild hepatic impairment; as an intact immunoglobulin, OBX-319 is not eliminated renally or hepatically to a clinically relevant degree (see section 5.2). No data are available in severe renal or hepatic impairment. Elderly patients (≥65 years) require no dose adjustment; data in the very elderly are limited. The safety and efficacy of OBX-319 in children and adolescents (<18 years) have not been established. For use in pregnancy and lactation, refer to the product information; as a human IgG1, OBX-319 is expected to cross the placenta, particularly in the second and third trimesters.

Method of administration. OBX-319 is administered subcutaneously, with injection sites (e.g., abdomen or thigh) rotated between administrations. After appropriate training in subcutaneous injection technique and recognition of reactions requiring medical attention, administration by the patient or caregiver may be appropriate where permitted by the approved product information.

4.3 Contraindications.

• Known serious hypersensitivity to the active substance or to any of the excipients.
• Active serious infection, including active tuberculosis, and other clinically significant active infection (e.g., active hepatitis B), until adequately treated and resolved.

5.1 Pharmacodynamic properties.

Pharmacotherapeutic group: Selective immunosuppressants. ATC code: not yet assigned.

Mechanism of action. OBX-319 is a humanized bispecific IgG1 monoclonal antibody, produced in Chinese hamster ovary (CHO) cells by recombinant DNA technology, that binds simultaneously to CD19 and CD20 on the surface of B-lineage cells. Co-engagement of the two B-cell antigens by a single molecule promotes high-avidity binding across a broad range of B-cell developmental stages — CD19 extends coverage to earlier and later stages of the B lineage (including a portion of plasmablasts) beyond the CD20-restricted window — and drives near-complete B-cell depletion through Fc-mediated effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). Depletion of autoreactive B cells reduces the pool of autoantibody-secreting cells implicated in the pathogenesis of SLE.

Pharmacodynamic effects. In OBX319-301, both active dose arms produced near-complete depletion of circulating CD19+ B cells, with mean counts falling from approximately 210 cells/µL at baseline to approximately 7 cells/µL, whereas B-cell counts remained essentially unchanged on placebo. Depletion was accompanied by improvement in serological markers of disease activity: anti-dsDNA antibody titres declined and complement C3 and C4 normalised in patients who responded to treatment. Sustained B-cell depletion may be associated with reductions in serum immunoglobulins over time (see section 4.2).

Clinical efficacy and safety. Efficacy and safety were evaluated in OBX319-301, a Phase 3, randomized, double-blind, placebo-controlled study in 480 adults with moderate-to-severe active SLE receiving background standard-of-care. Patients were randomized 1:1:1 to OBX-319 High (n=162), OBX-319 Low (n=158) or placebo (n=160) and treated for 52 weeks. The mean baseline SLEDAI-2K was approximately 11, consistent with moderate-to-severe active disease. The primary objective was to demonstrate reduction in disease activity, assessed by the change in SLEDAI-2K and by attainment of low disease activity (SLEDAI-2K ≤ 4) at Week 52.

Both OBX-319 dose arms were superior to placebo for the change in SLEDAI-2K at Week 52:

Arm	N	LS-mean Δ SLEDAI-2K @ Wk 52 (points)	Diff vs placebo (95% CI)	p
OBX-319 High	162	-6.37	-2.91 (-3.12, -2.69)	0.0000
OBX-319 Low	158	-5.62	-2.17 (-2.38, -1.95)	0.0000
Placebo	160	-3.46	— (reference)	—

Responder analysis — Low disease activity (SLEDAI-2K <= 4)

Arm	N	Responders, n/N	Rate	Risk diff vs placebo (95% CI, %)	p
OBX-319 High	145	76/145	52.4%	46.4% (37.4, 55.4)	0.0000
OBX-319 Low	145	49/145	33.8%	27.8% (19.2, 36.4)	0.0000
Placebo	150	9/150	6.0%	— (reference)	—

A dose-ordered effect was observed, with the High dose producing the larger reduction in SLEDAI-2K and the higher proportion of patients achieving low disease activity. The efficacy findings were internally consistent with the pharmacodynamic effects (B-cell depletion, falling anti-dsDNA and normalising complement).

Safety of the pharmacological class. Consistent with the known effects of profound B-cell depletion, the key identified risks are serious and opportunistic infections and hypogammaglobulinaemia. Injection-related reactions may occur. As with other therapeutic monoclonal antibodies, immunogenicity is expected: anti-drug antibodies (ADA), including neutralising antibodies, may develop and, in a subset of patients, could affect exposure, pharmacodynamics or the risk of hypersensitivity and injection reactions. Screening, vaccination and monitoring measures to mitigate these risks are described in sections 4.2 and 4.3.

Paediatric population. The European Medicines Agency has deferred the obligation to submit the results of studies with OBX-319 in one or more subsets of the paediatric population in SLE. See section 4.2 for information on paediatric use.

5.2 Pharmacokinetic properties. Following subcutaneous administration, OBX-319 is absorbed with a bioavailability typical of an intact IgG1 monoclonal antibody. The pharmacokinetics are non-linear as a consequence of target-mediated drug disposition (TMDD): at lower concentrations, saturable binding to CD19/CD20 on B cells contributes a receptor-mediated component of clearance, so that exposure increases more than dose-proportionally as the target-mediated pathway saturates and depletion of the B-cell sink is achieved; at higher concentrations, disposition is dominated by the linear, non-specific IgG pathway. Distribution is largely confined to the plasma and interstitial fluid, with a volume of distribution consistent with that of an immunoglobulin. Elimination occurs by proteolytic catabolism to small peptides and amino acids and, in the target-mediated component, by receptor-mediated clearance; recycling via the neonatal Fc receptor (FcRn) contributes to the long terminal half-life characteristic of IgG1 antibodies. Classical small-molecule ADME processes (mass-balance recovery, cytochrome P450 metabolism, and membrane-transporter–mediated disposition) are not applicable to an intact immunoglobulin, and no dedicated drug–drug interaction studies of these pathways are warranted.

Special populations and intrinsic/extrinsic factors. No clinically meaningful effect of age, mild-to-moderate renal impairment or mild hepatic impairment on exposure is expected, as OBX-319 is not cleared by renal or hepatic routes to a relevant extent. The development of ADA may increase clearance and lower exposure in affected patients (see section 5.1). Population pharmacokinetic characterisation supports the posology described in section 4.2.

Nonclinical pharmacokinetic context. The cynomolgus monkey was the sole pharmacologically relevant species for nonclinical characterisation, as OBX-319 does not cross-react with rodent CD19/CD20; nonclinical pharmacokinetics and safety were therefore evaluated in this species, consistent with ICH S6(R1). In line with the same guidance, genotoxicity, carcinogenicity and dedicated cardiovascular safety pharmacology studies (including hERG assessment and a thorough QT study) were not conducted, as they are not warranted for an intact monoclonal antibody.

QRD template; Directive 2001/83/EC.