Phase 3, Randomized, Double-Blind, Placebo-Controlled, Global Study (FORWARD) of Fostamatinib for the Treatment of Warm Antibody Autoimmune Hemolytic Anemia

Background Autoimmune hemolytic anemia (AIHA) is a rare, serious blood disorder in which the immune system produces antibodies leading to phagocytosis and destruction of red blood cells. Fostamatinib, a spleen tyrosine kinase inhibitor, blocks destruction of red blood cells and decreases B cell activation thereby reducing antibody production and epitope spreading. To date, there are no disease-targeted therapies approved for warm AIHA (wAIHA), despite the existing significant unmet medical need. Fostamatinib is approved for immune thrombocytopenia and is under investigation for wAIHA.

Methods The FORWARD trial is a Phase 3 randomized, double-blind, placebo-controlled clinical study of fostamatinib in patients with wAIHA who have failed at least one prior treatment. Fostamatinib was started at 100mg BID and increased to 150mg BID after 4 weeks if needed and tolerated. Up to 2 concomitant AIHA treatments were allowed. The primary endpoint was a durable hemoglobin (Hgb) response of ≥10 g/dL with an increase from baseline of ≥2 g/dL on 3 consecutive visits during the 24-week treatment period. The pre-specified analysis censored Hgb values attributable to rescue therapy received during the placebo-controlled treatment period. This reanalysis extended the pre-specified censoring rule for Hgb values to include the screening period. In addition, 2 patients who did not have evidence of hemolysis were excluded from the reanalysis.

Results The study randomized 90 patients to fostamatinib (n=45) or placebo (n=45) with patient median age 58 and 64 years, and median (range) duration of wAIHA of 1.7 (0.16-29.2) and 2.6 (0.1-23.1) years, respectively. The primary endpoint of durable Hgb response based on the original analysis method was not met in the overall population but was significant in the US, Canada, Australia, and Western European countries. Based on the reanalysis, the primary endpoint was met by 15/45 (33.3%) patients receiving fostamatinib, which is statistically significantly better than the 6/43 (14.0%) patients receiving placebo (p<0.0395) (Table 1). All 6 placebo responders were from Eastern Europe, and a regional analysis was conducted. The durable Hgb response rate with fostamatinib in the US, Canada, Australia, and Western Europe was significantly greater than with placebo (8/25 [32.0%] vs. 0/28, p=0.0021) (Table 1). The Hgb response rate with fostamatinib in Eastern Europe was not significantly different than placebo (7/20 [34.0%] vs 6/15 [40%]).

The safety profile of fostamatinib was consistent with prior clinical experience with no new safety findings. The most common adverse events (AEs in ≥10% of patients) with fostamatinib and placebo were diarrhea (26.7% and 6.7%), hypertension (24.4% and 17.8%), fatigue (15.6% and 11.1%), pyrexia (13.3% and 6.7%), nausea (13.3% and 8.9%), and dyspnea (13.3% and 11.1%) (Table 2).

Conclusions There was considerable use of rescue medications during the screening period leading to a high placebo response rate. Extending pre-specified censoring rules to the screening period yielded a statistically significant efficacy result overall and a highly significant result in Western Countries. The safety profile was generally consistent with the existing package insert for fostamatinib.

Kuter:Immunovant: Consultancy, Research Funding; Alnylam: Consultancy, Research Funding; Kezar: Research Funding; Principia: Consultancy, Research Funding; Protalex: Consultancy, Research Funding; CRICO: Consultancy; Caremark: Consultancy; Rigel: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda (Bioverativ): Consultancy, Research Funding; UCB: Consultancy, Research Funding; BioCryst: Consultancy, Research Funding; Agios: Consultancy, Research Funding; Hengrui: Consultancy; Cellphire: Consultancy; Cellularity: Consultancy; Platelet Biogenesis: Consultancy; Rubius: Current holder of stock options in a privately-held company; Zafgen: Consultancy; Actelion (Syntimmune): Consultancy, Research Funding; argenx: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; Dova: Consultancy; Genzyme: Consultancy; Incyte: Consultancy; Kyowa Kirin: Consultancy; Merck Sharp & Dohme: Consultancy; Momenta: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; Platelet Disorder Support Association: Consultancy; Sanofi: Consultancy; Shionogi: Consultancy; Shire: Consultancy; Up-To-Date: Consultancy. Piatek:Oscotec: Research Funding; Dova: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Annexon Biosciences: Membership on an entity's Board of Directors or advisory committees; Alexion/AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Rigel Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Apellis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Argenx: Research Funding. Saikali:Rigel Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Dummer:Rigel Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company.

TAVALISSE (fostamatinib disodium hexahydrate) is a prescription medication used to treat adults with low platelet counts due to chronic immune thrombocytopenia (ITP) when a prior treatment for ITP has not worked well enough. It is not known if TAVALISSE is safe and effective in children.