Pb2625: vayhit2: a randomized, double-blind, phase iii trial of ianalumab vs placebo in addition to eltrombopag in patients with primary immune thrombocytopenia (itp) who failed first-line steroid treatment

Topic: 32. Platelet disorders Background: The pathophysiology of ITP is characterized by increased peripheral destruction of platelets and inappropriate platelet production in the bone marrow, with activated autoreactive B cells playing an important role. B-cell activating factor (BAFF) regulates differentiation, proliferation and survival of B cells through its interactions with the BAFF receptor (BAFF-R). Elevated serum BAFF levels in patients (pts) with ITP correspond with increased disease activity. Ianalumab is an investigational, fully human immunoglobulin G1 monoclonal antibody that targets BAFF-R and has a novel dual mechanism of action: depleting B cells by direct antibody-dependent cellular cytotoxicity and inhibiting B-cell functions through BAFF-R blockade. Thrombopoietin receptor agonists (TPO-RAs, eg eltrombopag [ETB]) are a standard second-line (2L) ITP treatment effective in increasing platelet count to safe levels but typically require a chronic treatment approach since only 25–30% of pts may achieve a maintained response after TPO-RAs are tapered and withdrawn (Lucchini et al 2019; Cooper EHA 2022). Aims: VAYHIT2 (NCT05653219, EudraCT no. 2022-001627-32) is a multicenter, randomized, double-blinded, Phase III study assessing whether the addition of ianalumab to short-term ETB administration, working with different and complementary mechanisms of action, can prolong time to treatment failure in pts with primary ITP compared with ETB monotherapy. Methods: VAYHIT2 will enroll approximately 150 participants. Eligible participants will have primary ITP with an insufficient response to, or relapse after, first-line corticosteroid therapy (+/− intravenous Ig [IVIg]). Participants must also have a platelet count <30 G/L, assessed need for 2L treatment and be eligible to receive ETB. Exclusion criteria include use of 2L ITP treatment (other than corticosteroid therapy +/− IVIg). Participants will be randomized in a 1:1:1 ratio to ETB plus a lower ianalumab dose, a higher ianalumab dose or placebo. Ianalumab or placebo will be administered intravenously every 4 weeks. ETB will be administered orally to all participants once daily and tapered after the double-blinded treatment period in pts with stable platelet counts ≥50 G/L (Figure). After the treatment period, participants will be monitored for efficacy until treatment failure and for safety during a follow-up period of up to 2 years. The primary endpoint is the time from randomization to treatment failure, defined as platelet count <30 G/L or need for a rescue treatment (eg corticosteroids, IVIg or platelet transfusion) later than 8 weeks from randomization, the start of new ITP treatment, ineligibility to taper or inability to discontinue ETB, or death. The secondary endpoints include complete response (CR) and response (R) rate (proportion of participants with any platelet count of ≥100 G/L and ≥50 G/L, respectively, in the absence of rescue or new ITP treatment), time to R and CR, frequency of bleeding and adverse events, use of rescue treatments, rate of pts able to successfully discontinue ETB, pt-reported outcomes, pharmacokinetics and immunogenicity of ianalumab, and B-cell and immunoglobulin levels.Results: At the time of writing, no pts have been randomized into the VAYHIT2 study. Summary/Conclusion: The Phase III VAYHIT2 study will evaluate the ability of ianalumab in addition to a short ETB treatment to prolong time to treatment failure. Keywords: Monoclonal antibody, BAFF, Phase III, Immune thrombocytopenia (ITP)