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Patient Narratives (OBX319-301)

Document ID: CSR-301-16.3
Version: 1.0
Change History: 1.0 — Initial issue.
Standard(s): ICH E3 §16.3

Patient Narratives (CSR §16.3) — OBX319-301

Narratives for each death, serious adverse event, and other significant adverse event in OBX319-301, giving subject, treatment, event term, onset/course, management, outcome, and causality assessment, per ICH E3 §16.3.

Scope and methodology

OBX-319 is a humanized IgG1 bispecific monoclonal antibody that simultaneously engages CD19 and CD20 on the B-cell surface, producing broad depletion across the B-lineage (from pre-B through memory B cells and short-lived plasmablasts) via Fc-mediated effector function (antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity). Because both targets are B-cell antigens, the molecule is a depleting antibody rather than a T-cell–redirecting engager; cytokine release syndrome is therefore not a mechanistically expected feature, and none was observed in this study. The anticipated risks derive from the pharmacology of sustained B-cell depletion — serious and opportunistic infections and secondary hypogammaglobulinaemia (the key identified risks) — together with subcutaneous administration (injection-site and hypersensitivity reactions) and immunogenicity (anti-drug antibodies, ADA). Consistent with a monoclonal antibody, no adverse events attributable to genotoxicity, QT prolongation, or thyroid effects were expected or reported.

Narratives were prepared for every subject in the safety population who died, who experienced a treatment-emergent serious adverse event (SAE), or who experienced an "other significant" adverse event as defined by ICH E3 §16.3 (an adverse event leading to discontinuation of study treatment, dose interruption, or a marked laboratory abnormality of clinical importance). Of the 480 randomized subjects (162 OBX-319 High-dose, 158 OBX-319 Low-dose, 160 placebo), the events meeting narrative criteria, consistent with the safety summary in CSR §12, were: 1 death (OBX-319 High-dose); SAEs in 4 subjects (2 OBX-319 High-dose, of whom 1 was the fatal case; 1 OBX-319 Low-dose; 1 placebo); and study-treatment discontinuations in 17 OBX-319 High-dose, 13 OBX-319 Low-dose, and 10 placebo subjects, of which the clinically important adverse-event–related discontinuations are narrated below. Full narratives for all subjects meeting criteria are compiled in this section; the representative index cases for each category are presented in detail here, and the remaining narratives follow the identical structure with cross-reference to the by-subject data listings in Appendix 16.2 and the safety tabulations in CSR §12.

Narrative conventions

• Subject identifier is given as site–subject (format 301-SSSS-NNNN); the treatment arm shown is the unblinded randomized assignment.
• Study Day 1 is the day of the first subcutaneous dose. Study treatment (active or matching placebo) was administered subcutaneously at Weeks 0, 2, and 4 and every 4 weeks thereafter through Week 48, on background standard-of-care (glucocorticoids, antimalarials, and/or immunosuppressants). Study weeks are given alongside study days for orientation.
• Pharmacodynamic context. On the active arms, peripheral CD19+ B cells declined from a baseline of approximately 210 cells/µL to approximately 7 cells/µL, with parallel reductions in anti-dsDNA and normalisation of complement C3/C4 in responders; placebo subjects showed no material change in CD19+ B-cell count. Per-subject values are cited where relevant to the event.
• Causality is reported as assessed by the investigator and, separately, by the sponsor, using the categories Related / Possibly related / Unlikely related / Not related. Action taken with study treatment is reported as Withdrawn / Interrupted / Dose not changed. Outcome uses the categories Fatal / Not recovered / Recovering / Recovered with sequelae / Recovered.
• Immunogenicity status (ADA) and, where obtained, neutralizing-antibody status are reported for events with a plausible hypersensitivity or loss-of-effect component, consistent with the target-mediated drug disposition (TMDD) pharmacokinetics of the molecule.

16.3.1 Deaths

Subject 301-2071-0043 — OBX-319 High-dose — fatal bacterial pneumonia with septic shock. A 61-year-old woman with a 9-year history of Systemic Lupus Erythematosus, including prior biopsy-proven Class IV lupus nephritis in sustained renal remission, entered the study with a SLEDAI-2K of 12 on background mycophenolate mofetil 2 g/day, prednisone 7.5 mg/day, and hydroxychloroquine. Screening baseline CD19+ B-cell count was 205 cells/µL and serum IgG was 7.8 g/L. Following initiation of subcutaneous OBX-319 on Day 1, peripheral CD19+ B cells depleted to below 10 cells/µL by Week 4; serial monitoring showed a progressive decline in serum IgG to 4.1 g/L (below the lower limit of normal of 6.0 g/L) by Week 20, consistent with secondary hypogammaglobulinaemia. On approximately Day 172 (Week 25) the subject developed fever, rigors, and productive cough; she was admitted on Day 174 with lobar community-acquired pneumonia (initial sputum and blood cultures growing Streptococcus pneumoniae, with subsequent gram-negative superinfection). Despite broad-spectrum intravenous antibiotics, intensive-care support, and mechanical ventilation, the course progressed to respiratory failure and refractory septic shock, and the subject died on Day 189. The event met the seriousness criteria of death, hospitalization, and life-threatening. The investigator assessed the event as related to study treatment, attributing the increased infection susceptibility to B-cell depletion with secondary hypogammaglobulinaemia; the sponsor concurred that study treatment was contributory. Study treatment had been permanently withdrawn at hospitalization on Day 174. Outcome: fatal. This case is representative of the serious-infection risk that constitutes the principal identified safety concern for B-cell–depleting therapy in this population.

16.3.2 Non-fatal serious adverse events

Subject 301-2071-0210 — OBX-319 High-dose — multi-dermatomal herpes zoster. A 39-year-old woman with a 4-year history of SLE (predominantly mucocutaneous and articular), baseline SLEDAI-2K 10, on hydroxychloroquine, prednisone 10 mg/day, and azathioprine, was varicella-zoster-virus IgG seropositive at screening. On the High-dose arm her CD19+ B cells depleted to approximately 6 cells/µL by Week 4. On Day 98 (Week 14) she developed a painful vesicular eruption spanning two contiguous thoracic dermatomes; she was admitted on Day 100 for intravenous aciclovir. There was no ophthalmic or visceral dissemination and no encephalitic features. The event met the seriousness criterion of hospitalization. The investigator and sponsor assessed the event as related to study treatment, consistent with the recognised risk of opportunistic viral reactivation during B-cell depletion. Study treatment was interrupted at diagnosis and resumed on Day 130 after cutaneous healing; residual post-herpetic neuralgia was managed with gabapentin. Outcome: recovered with sequelae (mild post-herpetic neuralgia).

Subject 301-1150-0301 — OBX-319 Low-dose — acute pyelonephritis with urosepsis. A 52-year-old woman with a 7-year history of SLE and a background of recurrent uncomplicated urinary tract infections, baseline SLEDAI-2K 11, on mycophenolate mofetil and prednisone 5 mg/day, was randomized to the Low-dose arm; her CD19+ B cells depleted to approximately 8 cells/µL. On Day 205 (Week 29) she developed high fever, flank pain, and dysuria; she was admitted on Day 206 with acute pyelonephritis and Escherichia coli bacteraemia complicated by transient hypotension (urosepsis). The event met the seriousness criterion of hospitalization. She responded promptly to intravenous antibiotics and fluid resuscitation and recovered fully by Day 214. The investigator and sponsor assessed the event as related to study treatment in the context of B-cell depletion. Study treatment was interrupted during the admission and resumed after resolution. Outcome: recovered.

Subject 301-3004-0233 — Placebo — proliferative lupus nephritis flare. A 41-year-old woman with a 5-year history of SLE and prior lupus nephritis, baseline SLEDAI-2K 13, on mycophenolate mofetil, prednisone 10 mg/day, and hydroxychloroquine, was randomized to placebo; her CD19+ B-cell count remained unchanged (approximately 215 cells/µL) throughout, as expected in the absence of active treatment. From approximately Day 140 she developed rising proteinuria, increasing anti-dsDNA titres, and falling complement C3/C4 with an active urinary sediment; a repeat renal biopsy on Day 156 confirmed a proliferative (Class III/IV) lupus nephritis flare. She was admitted on Day 158 for intravenous methylprednisolone followed by induction immunosuppression. The event met the seriousness criterion of hospitalization. The investigator and sponsor assessed the event as not related to study treatment, attributing it to progression of underlying lupus nephritis; the presentation is consistent with the higher frequency of lupus nephritis flare observed on the placebo arm. Study treatment was withdrawn and rescue therapy initiated. Outcome: recovering.

16.3.3 Other significant adverse events

Narratives in this subsection cover clinically important adverse events that led to discontinuation of study treatment, dose interruption, or a marked laboratory abnormality, drawn from the 17 OBX-319 High-dose, 13 OBX-319 Low-dose, and 10 placebo discontinuations reported in CSR §12. The remaining discontinuation narratives follow the identical structure.

Subject 301-2071-0301 — OBX-319 High-dose — recurrent injection-site reactions leading to withdrawal. A 45-year-old woman with a 6-year history of SLE, baseline SLEDAI-2K 9, experienced Grade 2 injection-site reactions (erythema, induration, and pruritus at the subcutaneous injection site) recurring after successive doses on Days 15, 43, and 71. The reactions were non-serious, self-limiting over 48–72 hours, and managed with oral antihistamines and topical corticosteroids. In view of the recurrent local intolerance the subject elected, with the investigator, to discontinue study treatment on Day 78. The investigator assessed the reactions as related to study treatment; the sponsor concurred. These events are representative of the injection-site reactions expected with subcutaneous administration and observed more frequently on the High-dose arm. Outcome: recovered.

Subject 301-4012-0077 — OBX-319 High-dose — secondary hypogammaglobulinaemia leading to protocol-defined discontinuation. A 47-year-old woman with an 8-year history of SLE, baseline SLEDAI-2K 12, on mycophenolate mofetil and prednisone 7.5 mg/day, maintained near-complete CD19+ B-cell depletion (approximately 7 cells/µL). Serial immunoglobulin monitoring showed a decline in serum IgG from 6.9 g/L at baseline to 3.6 g/L by Week 28 (below the protocol-specified immunoglobulin threshold), accompanied by two lower-respiratory-tract infections managed on an outpatient basis. In accordance with the protocol-mandated immunoglobulin-monitoring rule, study treatment was discontinued on Day 210 and immunoglobulin replacement therapy was initiated. The investigator and sponsor assessed the hypogammaglobulinaemia as related to study treatment, consistent with the identified risk of sustained B-cell depletion. Outcome: recovering on immunoglobulin replacement.

Subject 301-3040-0159 — OBX-319 Low-dose — anti-drug-antibody–associated systemic hypersensitivity leading to discontinuation. A 34-year-old woman with a 3-year history of SLE, baseline SLEDAI-2K 10, developed treatment-emergent anti-drug antibodies (high titre, confirmed neutralizing) by Week 16. At the Day 116 dose she experienced generalised urticaria, facial flushing, and mild bronchospasm (Grade 2) shortly after subcutaneous administration; the reaction resolved the same day with an oral antihistamine and a single dose of corticosteroid and did not require hospitalization (non-serious). Given the combination of confirmed immunogenicity and a systemic hypersensitivity reaction, study treatment was discontinued on Day 116. Concurrent pharmacodynamic sampling showed attenuation of B-cell depletion attributable to the neutralizing ADA response, with partial recovery of the CD19+ B-cell count to approximately 40 cells/µL. The investigator and sponsor assessed the event as related to study treatment. Outcome: recovered. This case illustrates the interrelated immunogenicity and hypersensitivity risks relevant to a subcutaneous therapeutic antibody with TMDD pharmacokinetics.

Subject 301-1150-0255 — OBX-319 Low-dose — late-onset neutropenia leading to discontinuation. A 48-year-old woman with a 5-year history of SLE, baseline SLEDAI-2K 11, on concomitant mycophenolate mofetil, was found on routine haematology on Day 224 to have Grade 3 neutropenia (absolute neutrophil count nadir 0.8 × 10⁹/L). The finding was asymptomatic with no associated infection. Study treatment was interrupted and subsequently discontinued at the investigator's discretion; the neutrophil count recovered to normal by Day 245 without granulocyte colony-stimulating factor support. The investigator assessed the event as possibly related to study treatment, confounded by concomitant mycophenolate mofetil; the sponsor concurred. Outcome: recovered.

Subject 301-3004-0141 — Placebo — disease worsening leading to discontinuation. A 44-year-old woman with a 5-year history of SLE, baseline SLEDAI-2K 12, on hydroxychloroquine and prednisone, was randomized to placebo. Over Weeks 8–16 she experienced progressive articular and mucocutaneous disease activity with a rising SLEDAI-2K; her CD19+ B-cell count was unchanged, as expected. On Day 120 the investigator discontinued study treatment for disease worsening and inadequate control and initiated rescue immunosuppression. The event was assessed as not related to study treatment, reflecting underlying disease progression. Outcome: recovering on rescue therapy. The case is representative of the disease-driven discontinuations observed on the placebo arm.

Cross-reference and safety context

The narratives above characterise the events that shaped the benefit–risk assessment of OBX-319 over the 52-week induction period: a single fatal serious infection and the non-fatal serious infections (multi-dermatomal herpes zoster, pyelonephritis with urosepsis) that, together with secondary hypogammaglobulinaemia, embody the key identified risks of B-cell depletion; the injection-site and hypersensitivity reactions and the associated immunogenicity expected of a subcutaneously administered therapeutic antibody; and the disease-driven serious events and discontinuations, which predominated on placebo. No cytokine release syndrome, and no events attributable to thyroid, cardiac-repolarisation (QT), or genotoxic mechanisms, were reported, consistent with the pharmacology of the molecule. These narratives are to be read together with the safety tabulations in CSR §12, the by-subject adverse-event and laboratory listings in Appendix 16.2, and the individual subject data in Appendix 16.4. ICH E3 §16.3.