Abstract
Introduction Primary immune thrombocytopenia (ITP) remains an area of unmet clinical need, particularly for patients who are refractory to multiple lines of therapy. Ianalumab, a fully human IgG1 monoclonal antibody that binds the B cell-activating factor receptor (BAFF-R), offers a dual mechanism of action by depleting B cells through enhanced antibody-dependent cellular cytotoxicity (ADCC) with concurrent blockade of the BAFF:BAFF-R signaling pathway. The primary analysis of the VAYHIT3 study (NCT05885555) suggested that a short course of ianalumab was effective and well tolerated in heavily pretreated patients with primary ITP. Nearly half (44%) of the patients achieved a confirmed response (ConfR), and more than half (56%) of these responders maintained a stable response (SR) at 6 months. No new safety signals were observed up to the primary analysis data cutoff. Here we present the main secondary analyses, including subgroup evaluations, from the primary VAYHIT3 results.
Methods This Phase 2, open-label, single-arm study enrolled adults with primary ITP and a platelet count <30 G/L, previously treated with at least a corticosteroid (CS) and a thrombopoietin receptor agonist (TPO-RA). Patients who had prior splenectomy were excluded. Patients received 4 doses of ianalumab, 9 mg/kg intravenously, once every 4 weeks; current therapy with CS and/or TPO-RA could be continued if clinically indicated and if the dose was stable ≥14 days before ianalumab initiation. The primary endpoint is ConfR, defined as a platelet count of ≥50 G/L at 2 or more consecutive assessments at least 7 days apart between Weeks 1 and 25, in the absence of rescue or new treatment. The primary efficacy endpoint was analyzed by subgroups: prior ITP treatments (2‒3, 4‒5, ≥6), age (18‒<65, ≥65 years), and sex (male, female). Secondary objectives included assessment of quality of response and safety. Responses assessed in the study included SR, defined as a platelet count of ≥50 G/L on at least 75% of assessments between Weeks 19 and 25, in the absence of rescue or new treatment, and complete response (CR), defined as a platelet count of ≥100 G/L in the absence of rescue or new treatment.
Results At primary analysis data cutoff, all 41 enrolled patients had either completed Week 25 of the study or discontinued earlier. The median age was 55 years, and 51% of participants were female. The median number of prior lines of therapy was 6 (range: 2‒13), with 36 patients (88%) having received ≥4 prior lines. At study entry, most patients continued with current therapies, with 14 patients (34%) remaining on CS and 21 patients (51%) on TPO-RAs. Of the 41 patients, 38 (93%) received all four planned infusions of ianalumab. Two patients (5%) received two infusions, and one patient (2%) received only one infusion; the reasons for not receiving infusions were lack of therapeutic effect and patient decision. Rapid and potent B-cell depletion was observed, with a median percent change from baseline of –97.6% at Week 5 (prior to the second infusion) and –99.9% at Week 13 (prior to the fourth infusion); median time to B-cell recovery was not estimable by data cutoff. At Week 25, ConfR rates suggested benefit across all subgroups, including prior ITP treatments (2‒3, 40%; 4‒5, 67%; ≥6, 33%), age (18‒<65 years, 42%; ≥65 years, 50%), and sex (female, 48%; male, 40%). The proportion of patients with CR increased from 10% at Week 9 to 22% at Week 25. All but one patient maintained IgG values ≥5 g/L post-baseline. At baseline, 24 patients (59%) reported bleeding events per the WHO Bleeding Scale, with most being Grade 1 (44%). From the second infusion onward, reported bleeding events significantly reduced, and by Week 25, only 8/37 evaluable patients (22%) reported any-grade bleeding events, with most being Grade 1 (6/37, 16%). With longer follow-up, no new safety signals were observed.
Conclusion These secondary analyses support the efficacy profile of ianalumab in heavily pretreated patients with primary ITP. The treatment demonstrated fast and profound B-cell depletion, as well as consistent benefits across subgroups, with improvements in bleeding symptoms.
