A Phase III Clinical Trial Program Investigating the Efficacy and Safety of Ianalumab in Patients with Primary Immune Thrombocytopenia (VAYHIT1 and VAYHIT2) and Warm Autoimmune Hemolytic Anemia (VAYHIA)

Background: Immune thrombocytopenia (ITP) and warm autoimmune hemolytic anemia (wAIHA) are characterized by autoantibody destruction of platelets and red blood cells, respectively. Autoreactive B cells play a role in the pathophysiology of ITP and wAIHA. Serum levels of B-cell activating factor (BAFF) are elevated in these disorders and correlate with increased disease activity. Ianalumab is a novel, fully human immunoglobulin G1 monoclonal antibody that targets BAFF receptor (BAFF-R) and has a unique dual mechanism of action: direct antibody-dependent cellular cytotoxicity-mediated B-cell depletion and inhibition of B-cell differentiation, proliferation and survival via blockade of BAFF-R-mediated signaling. Corticosteroids (CS) are the standard first-line treatment for ITP; however, few patients achieve a long-term response. Additionally, extended and recurrent use of CS is associated with substantial toxicity. Thrombopoietin receptor agonists (TPO-RAs), such as eltrombopag, are commonly used second-line ITP treatments and often achieve a response; however, responses are rarely maintained once treatment ends, so chronic administration is typically required. For wAIHA, few treatments have been approved, and patients rarely achieve durable responses on CS or off-label rituximab. Thus, there are significant unmet needs for patients with ITP or wAIHA.

Aim: We report the designs of the randomized, double-blind, multicenter, 3-arm Phase III VAYHIT1 (NCT05653349), VAYHIT2 (NCT05653219) and VAYHIA (NCT05648968) trials. The trials aim to assess whether ianalumab, working with a distinct and complementary mechanism to standard-of-care treatments, can induce durable responses in patients with ITP or wAIHA.

Trial designs:

VAYHIT1 and VAYHIT2 will assess the efficacy and safety of ianalumab vs placebo in addition to first-line CS and short-term eltrombopag, respectively, in adults with primary ITP. In both trials, patients will be randomized 1:1:1 to intravenous (IV) low-dose ianalumab, high-dose ianalumab or placebo every 4 weeks (wks). The primary endpoint in both trials is the time from randomization to treatment failure, defined as platelet count <30 G/L later than 8 wks from randomization, need for rescue treatment later than 8 wks from randomization, start of a new ITP therapy, or death. In VAYHIT2, ineligibility to taper or inability to discontinue eltrombopag after the completion of treatment with ianalumab or placebo will also be assessed as treatment failure. Secondary endpoints include response rate, complete response rate and safety ( Table).

VAYHIA will assess the efficacy and safety of ianalumab vs placebo in adults with wAIHA who have failed ≥1 treatment. Patients will be randomized 1:1:1 to IV low-dose ianalumab, high-dose ianalumab or placebo every 4 wks. Selected supportive care is allowed. The primary endpoint is durable hemoglobin (Hb) response, defined as Hb ≥10 g/dL and an Hb increase of ≥2 g/dL from baseline for ≥8 consecutive wks between Wk 9 and Wk 25 in the absence of rescue or prohibited treatment. The key secondary endpoint is duration of durable Hb response ( Table). An optional open-label crossover period will allow patients who receive placebo and do not achieve a durable Hb response to receive high-dose ianalumab.

Patients from all 3 trials will be monitored for efficacy until treatment failure (or up to 39 months after the last patient was randomized, whichever comes first) and safety for up to 2 years.

Conclusions: These trials have been designed based on the hypothesis that, when administered early in disease progression, medical therapy targeting complementary physiological pathways may restore self-tolerance in patients with ITP and wAIHA. Ianalumab in combination with standard of care is expected to safely induce a high response rate that will be maintained beyond treatment completion. Ianalumab may address the unmet needs for patients with ITP and wAIHA.

Current status: At the time of writing, VAYHIT1, VAYHIT2 and VAYHIA are recruiting. The open-label, single-arm, Phase II VAYHIT3 trial is also assessing ianalumab in patients with primary ITP previously treated with at least 1 CS and 1 TPO-RA (NCT05885555).