Fostamatinib for the treatment of warm antibody autoimmune hemolytic anemia (waiha): Updates from the phase 2 and phase 3 clinical trials
Authors: D. Kuter, S. Tong
Journal: HemaSphere (2021)

Background: Warm antibody autoimmune hemolytic anemia (wAIHA) currently has no approved treatment options and is a rare, potentially serious disorder. The disease is characterized by red blood cell (RBC) phagocytosis in macrophages via a spleen tyrosine kinase (SYK) dependent signaling pathway. Fostamatinib, a potent oral SYK inhibitor, prevents SYK-dependent platelet phagocytosis in immune thrombocytopenia (ITP) and is an approved treatment for ITP. Fostamatinib may also prevent SYK dependent RBC phagocytosis in wAIHA. Aims: We conducted subgroup analyses of the phase 2, open-label study (NCT02612558) to better understand factors related to response to fostamatinib in patients with wAIHA. We also provide an update on the phase 3, randomized, double-blind, placebo-controlled, global study (NCT03764618) of fostamatinib for wAIHA including a Data Monitoring Committee (DMC) review of blinded data. Methods: Both studies enrolled (or are enrolling) adult patients with a diagnosis of primary/secondary wAIHA (documented by a positive direct antiglobulin test);baseline hemoglobin level ≤10 g/dL. Exclusion Criteria include (but are not limited to): presence of other forms of AIHA;uncontrolled hypertension. Hemoglobin (Hgb) response was defined as Hgb ≥10 g/dL with a ≥2 g/dL increase from baseline without rescue therapy. The Phase 2 study treated patients for up to 24 weeks at 150 mg BID. The phase 3 study is currently enrolling patients. During the 24-week study, eligible patients are randomized 1:1 to received fostamatinib or placebo. Randomization is stratified by concomitant steroid use and severity of anemia at baseline. The starting dose of 100 mg BID is increased to 150 mg BID after 4 weeks if drug is tolerated. Two concurrent wAIHA therapies are permitted during the study. A steroid taper protocol is implemented in patients with a Hgb response, and rescue therapy is allowed as needed. Patients can rollover to an open-label extension study upon completion of the randomized phase. Results: In the phase 2 studies, 44% (11/25) of patients had a Hgb Response by Week 24. In total, 48% responded as there was one late responder at Week 30 (12/25). Common adverse events (AEs) were diarrhea and hypertension. In a subgroup analysis, patients with secondary wAIHA (4/5 [80%]) appeared to respond better than patients with primary wAIHA (7/19 [37%]). Patients who received fostamatinib as second-line therapy (one prior wAIHA treatment) (6/9 [67%]) appeared to respond better than those who received fostamatinib as third-or-laterline therapy (>1 prior treatment) (5/15 [33%]). Female patients (8/14 [57%]) appeared to respond better than male patients (3/10 [30%]). Small sample sizes make it difficult to draw conclusions. Patient enrollment in the phase 3 study began last year. The study will enroll approximately 90 patients at 103 sites in 22 countries. As of January 11, 2021, 62 of 99 sites are open to screening (subject to local COVID-19 regulations), and 64 of 90 patients (71%) have been randomized. The DMC Review of data in 43 patients is shown in the table below. Summary/Conclusion: Fostamatinib markedly improved Hgb levels in 48% of 25 evaluable patients with wAIHA in phase 2 studies. The AEs observed in the phase 2 study are consistent with the fostamatinib safety database of >3500 patients across different diseases. The subgroup analyses in the phase 2 study were consistent with response rates in the larger ITP studies with regard to improved response rates with earlier line fostamatinib use. The results of the larger phase 3 study may help identify factors associated with better outcomes.