First line therapy for primary immune thrombocytopenia — beyond steroids…

STUDY TITLE: Study of Ianalumab Versus Placebo in Addition to First-line Corticosteroids in Primary Immune Thrombocytopenia (ITP) (VAYHIT1)

CLINICALTRIALS.GOV IDENTIFIER: NCT05653349

PARTICIPATING CENTERS: International study with 127 participating centers in North America, South America, Europe, Asia, and Australia

SPONSOR: Novartis Pharmaceuticals

ACCRUAL GOAL: A total of 225 participants between cohorts

STUDY DESIGN: VAYHIT1 is a phase III, double-blind, randomized, multicenter clinical trial designed to examine the efficacy and safety of ianalumab (a novel anti-B-cell activating factor [BAFF] receptor [BAFF-R] monoclonal antibody [mAb] in development for immune thrombocytopenia [ITP]) at either a 3 or 9 mg/kg dose compared to placebo when given in combination with standard-of-care corticosteroids. The study is focused on adult patients with primary ITP in the first three months of diagnosis and initiating corticosteroids. The primary endpoint of this trial is time from randomization to treatment failure (TTF) — defined as 1) a platelet count <30 G/L later than eight weeks from randomization, 2) the need for any form of rescue therapy (treatment for ITP to induce rapid increase in platelet count) later than eight weeks from randomization, 3) an initiation of second-line ITP therapy, or 4) death — to determine whether a combination of standard-dose corticosteroids and either dose of ianalumab prolongs TTF. Secondary endpoints include response rate, time to and duration of complete response (CR), bleeding events, infection rate, and need for rescue treatment in each group. Additional correlative studies will include analysis of B-cell markers including absolute number of CD19+ B cells and immunoglobulins. Moreover, the pharmacokinetics and immunogenicity of ianalumab will also be evaluated.

RATIONALE: ITP is an acquired platelet disorder characterized by immune-mediated destruction of platelets, leading to varying degrees of thrombocytopenia and increased bleeding risk. Primary ITP is defined as the absence of alternative etiologies or disease contributing to the thrombocytopenia. The disease has multimodal incidence, peaking during childhood and young adulthood, and among the elderly, with the highest age-specific incidence seen in those over age 60. Clinical manifestations of ITP become more critical when platelet counts drop below 20 × 10⁹/L and present with mucocutaneous bleeding with evidence of petechiae, epistaxis, purpura, and occasionally catastrophic bleeding in intracranial or gastrointestinal areas.

The pathophysiology underlying ITP relates to increased immune-mediated peripheral destruction of platelets and impaired megakaryocytopoiesis in the bone marrow. While the primary factors initiating primary ITP remain elusive, antiplatelet antibodies produced by autoreactive antibody-producing splenic B-lymphocytes play a critical role.¹  Antiplatelet antibodies directed against glycoproteins found on platelet and megakaryocyte surfaces lead to antibody-dependent cellular toxicity and complement cytotoxicity. Moreover, autoreactive T cells stimulated by splenic macrophages directly interact with autoreactive B cells, leading to enhanced proliferation and differentiation, further promoting antiplatelet antibody production.¹ 

Treatment for ITP is geared towards prevention of bleeding or resolving active bleeding by increasing platelet counts enough to achieve hemostasis, often at levels of 20-30 × 10⁹/L, while minimizing treatment-related toxicity. Management therefore includes pharmacotherapies that reduce immune-mediated destruction of platelets, including corticosteroids, intravenous immunoglobulins (IVIg), and rituximab.²  Despite high long-term remission rates, splenectomy is reserved for those patients who do not respond or stabilize after initial therapy due to concerns for thromboembolic and long-term infectious complications.³  Therapies that stimulate production of platelets, called thrombopoietin receptor agonists (TPO-RAs), or SyK inhibitors can be used during the chronic phase if immunosuppression is ineffective.

While the response to firstline therapy is great, 25% of patients will not respond and require alternative or additional therapies.^2,4  Only 20 to 30% of individuals who respond to initial corticosteroid therapy will sustain their response, subsequently requiring second- and third-line treatments.⁵  Ultimately, a significant proportion of patients either end up remaining on prolonged courses of corticosteroids or require multiple lines of treatment, compounding treatment toxicity. Moreover, with the introduction of each subsequent line of therapy, response rates decline and treatment may become more difficult, thus prompting the need for new disease-modifying therapies that can be used early on and accomplish a durable response.

As autoreactive B cells play an integral role in the pathophysiology of ITP, treatment directed towards inhibition of B-cell activation, proliferation, and differentiation presents a unique opportunity in the treatment of ITP. Ianalumab is a glycoengineered, fully human immunoglobulin G1 monoclonal antibody that directly targets and inhibits BAFF-R. It is increased in ITP, especially in refractory disease, and regulates proliferation, differentiation, and survival of B cells. Ianalumab acts by both inhibiting B-cell signaling and directly depleting B-cells through antibody-dependent cellular cytotoxicity.

In preclinical models, ianalumab enhanced antibody-dependent cellular toxicity (ADCC) against B cells and cytokine release, leading to a more profound depletion of B cells as compared to anti-CD20 antibodies (rituximab, ofatumumab, and obinutuzumab).⁶  While not yet studied in ITP, the rationale for using ianalumab in ITP stems from the results of clinical studies demonstrating efficacy in other autoimmune disorders. The original proof-of-concept (PoC) study demonstrated that single-dose intravenous ianalumab in a cohort of 27 patients with primary Sjögren’s Syndrome (pSS) led to a rapid and significant reduction in B cells and a clinically relevant reduction in disease severity.⁷  Additionally, a phase II clinical trial combining the anti-BAFF antibody belimumab with rituximab led to sustained responses for 12 months in 80% of individuals with systemic lupus erythematosus.⁸  Data from completed trials have demonstrated that treatment with ianalumab is well-tolerated, with minimal toxicity. The most frequently experienced side effects were infusion-/injection-related reactions and infections.

COMMENT: Traditionally, firstline therapy for primary ITP has been corticosteroids, which when used long-term are associated with profound treatment toxicity, poor response, and adverse patient outcomes. VAYHIT1 is designed to evaluate the efficacy and durability of ianalumab in the frontline setting for adults with primary ITP. If successful, this study can pave the way for a new era of therapy with a disease-modifying agent in combination with steroids to minimize toxicity and achieve durable response rates.