Clinical trial progress of fostatinib/fotantinib

Fostamatinib is an oral small molecule Syk (spleen tyrosine kinase) inhibitor originally developed by Rigel Pharmaceuticals and marketed in the United States under the brand name TAVALISSE for the treatment of refractory, chronic immune thrombocytopenia (ITP) in adults. On this basis, the drug is expanding into more areas of immune and blood diseases, post-transplantation complications and even infection-inflammation, and is currently in clinical trials at different stages in multiple indications.

1. Approved indications and research starting points

Two Phase 3 trials of fostamatinib in ITP (FIT-1 and FIT-2) clearly demonstrated a statistically significant advantage over placebo in long-term platelet recovery, leading to regulatory approval. In these trials, patients took 100 mg orally twice a day/can be increased to 150 mg twice a day if the effect was not achieved. During the 24-week observation period, the results showed that platelets increased steadily and side effects were controllable.

Based on this treatment platform, the R&D team will expand the application of Fostamatinib to warm antibody autoimmune hemolytic anemia (wAIHA), chronic GVHD (graft-versus-host disease) after hematopoietic stem cell transplantation, and even cancer associated with immunopathology or COVID-19-related inflammatory reactions.

2. Progress in trials of wAIHA (warm antibody autoimmune hemolytic anemia)

In the wAIHA space Rigel has initiated a Phase 3 pivotal trial (codename FORWARD) to explore fostamatinib in patients with wAIHA who have failed at least one prior therapy. The trial is a randomized, double-blind, placebo-controlled trial with a target enrollment of approximately 90 patients. In the trial design, the primary effect endpoint is "hemoglobin continues to rise above 10 g/dL, and at the same time it rises ≥2 g/dL compared to baseline, and meets the criteria for three consecutive examinations."

In its early phase Phase 2 open-label study, about 44% to 48% of patients achieved this indicator, showing a relatively promising efficacy signal. If Phase 3 results are positive, fostamatinib could become the first approved treatment in wAIHA.

3. Exploration of chronic graft-versus-host disease (cGVHD) and other indications

In terms of post-transplant complications, a Phase 1 trial used fostamatinib in patients with chronic GVHD, including prevention and treatment arms. In the study, 19 patients received the drug and the results showed an overall response rate of approximately 77%, of which approximately 31% achieved complete remission.

This suggests Fostamatinib has an early efficacy signal in GVHD and provides the basis for a subsequent Phase 2/3 trial.

4. New uses:Research during the COVID-19 outbreak

In addition to the fields of autoimmunity and transplantation, Fostamatinib is also being explored in severe lung injury and immune inflammation caused by COVID-19. A global multicenter Phase 3 randomized trial (Adults Hospitalized, Hypoxemic COVID-19) was conducted to assess improvement in the number of days without oxygen assistance in patients taking 150 mg orally twice daily.

The results showed thatFostamatinib group was not significantly better than placebo in the primary endpoint. The researchers pointed out that the effectiveness of the drug for this indication still needs more verification.

Taken together,Fostamatinib's clinical trial layout shows a "three-track advancement" situation: first, the approved indications (ITP); second, autoimmune/blood diseases (waAIHA, cGVHD) are in the critical phase 2/3; third, infection/inflammation (such as COVID-19) is being explored. Expanding trials have also shown the potential of the Syk signaling pathway in a variety of immunomodulatory pathological conditions. At the same time, judging from the experience of drug approval, its safety foundation is relatively solid, but each new indication faces challenges such as efficacy confirmation, dose optimization, and long-term safety monitoring.

Reference materials:https://go.drugbank.com/drugs/DB12010