A Phase 1b/ 2a study of budoprutug in patients with immune thrombocytopenia (ITP) Free

Background and Significance: Immune thrombocytopenia (ITP) is a rare disorder caused by accelerated, premature platelet destruction and impaired platelet production, leading to an increased risk of bleeding. Platelet destruction primarily results from binding by antiplatelet autoantibodies and removal by macrophages in the spleen and liver. Standard first-line treatment consists of corticosteroids with or without intravenous immunoglobulin (IVIG). Second-line options include either a recombinant human thrombopoietin receptor agonist (TPO-RA) or B-cell depletion using an anti-CD20 monoclonal antibody (mAb; rituximab). Approximately 80% of patients eventually fail first-line corticosteroid treatment and ~40% have continued disease progression with TPO-RAs. Rituximab may induce long-term disease remission, but only ~20% of patients maintain remission. New treatment options are needed that offer the potential for long-term remission of thrombocytopenia with a manageable safety and tolerability profile. CD19, unlike CD20, is expressed on plasma blasts and some plasma cells, and may offer advantages as a target for B-cell depletion in ITP. Budoprutug (TNT119) is a novel mAb that binds selectively to CD19 with picomolar affinity. It was bioengineered with a low-fucosylated Fc region for enhanced antibody-dependent cell cytotoxicity (ADCC). In an early clinical study in patients with primary membranous nephropathy, budoprutug administration demonstrated rapid and sustained B cell depletion, serologic remission, and resolution of proteinuria (Cortazar et al., ASN 2024), establishing proof-of-concept for budoprutug as a potential treatment approach in B-cell mediated disease.

Study Design and Methods: This Phase 1b/2a, open-label, sequential-cohort, dose escalation and expansion study (NCT07043946) will evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical effectiveness of budoprutug in approximately 24 patients with ITP. Budoprutug will be administered as two intravenous infusions 14 days apart in up to three ascending dose cohorts (n=6 per cohort) of patients aged 18 years and above with a platelet count < 30,000/µL despite an adequate trial of at least one prior therapeutic attempt. Each patient may receive an optional second cycle of budoprutug between Weeks 12 and 36 based on platelet response. Patients will be followed through Week 48 in the main study and will enter the long-term observational follow-up part of the study until B cell recovery. Following completion of the dose escalation phase, additional patients (n=6) will be enrolled into an expansion cohort at the dose identified during the dose escalation period.

• Primary safety endpoint: Incidence, relatedness, severity, and duration of treatment-emergent adverse events (TEAEs).

• Key secondary endpoints:

  • Budoprutug PK parameters

  • The change from baseline in absolute peripheral CD20+ B-cell count

  • The change from baseline in platelet count over time

  • The percentage of patients who achieve a stable, partial, or complete platelet response (defined as a platelet count ≥30,000/µL, ≥50,000/µL, or ≥100,000/µL, respectively, on at least 2 occasions at least 7 days apart within a 30-day time frame) up to Week 48.

The study is currently being conducted at multiple centers in Europe.

Conclusions: This Phase 1b/2a study will provide initial evidence regarding the safety and efficacy of CD19-targeted B-cell depletion with multiple doses of budoprutug in patients with ITP.