Ianalumab, a Novel Anti-B-Cell Activating Factor (BAFF) Receptor (BAFF-R) Monoclonal Antibody (mAb) in Development for Immune Thrombocytopenia (ITP) and Warm Autoimmune Hemolytic Anemia (wAIHA), Has Demonstrated a Favorable Safety Profile in Sjögren's Syndrome (SjS), Systemic Lupus Erythematosus (SLE) and Chronic Lymphocytic Leukemia (CLL)

Background: Current therapies for ITP and wAIHA are mostly symptomatic and rarely lead to durable responses after discontinuation; thus, chronic treatment is often needed, which may be associated with toxicity and substantial quality-of-life burden for patients. There is an unmet need for disease-modifying therapies that can induce and maintain durable responses beyond treatment completion in ITP and wAIHA. BAFF is an important regulator of B-cell differentiation, proliferation and survival through interactions with BAFF-R. Autoreactive B cells play a key role in the pathophysiology of ITP and wAIHA and are fueled by increased BAFF pathway activity; therefore, there is a strong rationale for investigating BAFF-R as a target in both diseases. Ianalumab is a fully human mAb that targets BAFF-R. It has a novel dual mechanism of action: blockade of BAFF-R-mediated signaling and potent depletion of B cells mediated by antibody-dependent cellular cytotoxicity. Ianalumab has shown favorable safety and encouraging efficacy in other indications, including SjS, SLE and CLL, and is a promising potential treatment for ITP and wAIHA. As ianalumab is being investigated in ongoing, blinded Phase III trials in ITP and wAIHA, we present the safety profile of ianalumab from completed Phase I/II studies in SjS, SLE or CLL.

Methods: Data for patients with SjS were from a randomized Phase IIb trial (NCT02962895); patients (N=190) received subcutaneous (SC) placebo or ianalumab 5, 50 or 300 mg every 4 weeks (wks) for 24 wks. Patients then entered a second treatment period; patients in the ianalumab 5 or 50 mg arm continued the same dose, patients in the ianalumab 300 mg arm were randomized to continue the same dose or receive placebo, and patients in the placebo arm switched to ianalumab 150 mg. Safety data in patients with SLE were collected from a randomized Phase II trial (NCT03656562). Patients (N=67) received SC ianalumab 300 mg or placebo every 4 wks for 28 wks; patients in the placebo group could switch to ianalumab in a 20-wk open-label extension. Data for patients with CLL were from a Phase Ib trial (NCT03400176); patients (N=32) received intravenous (IV) ianalumab 0.3, 1, 3 or 9 mg/kg every 2 wks plus ibrutinib 420 mg once daily for up to 8 28-day cycles. Safety assessments included adverse events (AEs), serious AEs (SAEs) and AEs of special interest.

Results: Ianalumab was safe and well tolerated in patients with SjS. Most AEs were mild or moderate in severity; severe AEs were reported in 5 patients receiving ianalumab. Three ianalumab-treated patients had SAEs; 2 SAEs in 1 patient (appendicitis and tubo-ovarian abscess) were considered related to ianalumab treatment. Frequency of infections/infestations was similar between patients treated with ianalumab and placebo. Discontinuation rates were low, with only 4 patients discontinuing ianalumab for non-serious AEs (infection [n=2], lymphopenia, local injection-site reaction [n=1 each]); no SAEs led to treatment discontinuation. Ianalumab continued to be well tolerated in the second treatment period. There were no dose-dependent differences in the rate of AEs except for injection-site reactions (mostly local and not severe).

In ianalumab-treated patients with SLE, there were no serious infections during the blinded period; only 1 SAE (renal impairment) was reported. In the open-label extension, 4 SAEs were reported. No SAEs in the blinded period or open-label extension were considered treatment related.

Most AEs in patients with CLL were Grade 1 or 2 and not correlated with dose. Twelve patients experienced Grade ≥3 AEs; decreased neutrophil count (n=5) was most common. No dose-limiting toxicities were reported.

Discussion: Data from patients with SjS, SLE or CLL receiving ianalumab for up to 52 wks show it has a favorable safety profile. There was a low risk of infections irrespective of dosing regimen. No cases of hypogammaglobulinemia were clinically significant in any trial. New treatments are needed for ITP and wAIHA that have disease-modifying potential and allow patients to achieve and maintain high response rates after a short therapeutic course. Ianalumab has the potential to address this unmet need and is currently being assessed as an IV dose every 4 wks in Phase III trials as both a first- (VAYHIT1 [NCT05653349]) and second-line (VAYHIT2 [NCT05653219]) treatment for ITP and as a second-line treatment for wAIHA (VAYHIA [NCT05648968]).